JP2010502569A - How to improve pharmacokinetics - Google Patents

Abstract

（式Ｉの化合物がアミノ基を含む場合にはその薬学的に許容し得るアンモニウム塩、式中、Ｒ_１は、例えば、Ｈ、（ＨＯ）_２Ｐ（Ｏ）−、（ＮａＯ）_２Ｐ（Ｏ）−、アルキル−ＣＯ−、又はシクロアルキル−ＣＯ−であることができ、Ｘは、例えば、Ｆ、Ｃｌ、及びＢｒであることでき、Ｒ２及びＲ３は、本明細書に定義した通りである）と前記薬物との併用投与を含む。The present invention provides pharmaceutical compositions and methods for improving the pharmacokinetics of drugs that can be metabolized by cytochrome P450 monooxygenase, the method comprising a compound of formula I:

(If the compound of formula I contains an amino group, its pharmaceutically acceptable ammonium salt, wherein R ₁ is, for example, H, (HO) ₂ P (O) —, (NaO) ₂ P ( O)-, alkyl-CO-, or cycloalkyl-CO-, X can be, for example, F, Cl, and Br, and R2 and R3 are as defined herein. And a combination administration of the above drugs.

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to methods and related pharmaceutical compositions for improving the pharmacokinetics of drugs metabolized by cytochrome P450 monooxygenase using PPL-100. In particular, the present invention relates to methods for improving the pharmacokinetics of HIV protease inhibitors by the combined administration of PPL-100 and such protease inhibitors.

BACKGROUND OF THE INVENTION HIV viral protease inhibitors have been developed in comparison in recent years and their use began in 1996. Currently, they are considered the most effective drugs against HIV infection. Unfortunately, most current protease inhibitors are relatively large hydrophobic molecules with fairly low bioavailability. Therefore, a heavy pill is needed to obtain a therapeutic dose in the patient. This is a deterrent and very often results in poor patient compliance and poor treatment results. This situation results in sub-optimal therapeutic drug concentrations, which in turn lead to the development of HIV resistant bacteria. As a result, there is a urgent need for improving the solubility and bioavailability of protease inhibitors.

  Examples of improved compounds are in the form of prodrugs of aspartyl protease inhibitors as described, for example, in US Pat. No. 6,436,989 to Hale et al., The entire contents of which are incorporated herein by reference. Has been developed. This patent represents a new class of molecules characterized by favorable water solubility, high oral bioavailability, and ease of in vivo production of active ingredients. However, it is well known that HIV has the ability to be resistant to currently available drugs. Therefore, there is a need for alternative HIV protease inhibitors that are active against wild-type and resistant virus bacteria. Thus, molecules derived from current HIV protease inhibitors that exhibit high solubility and bioavailability are desirable to combat resistant virus.

  A unique class of aromatic derivatives that are aspartyl protease inhibitors is described in US Patent No. 6,632,816 to Stranix et al., The entire contents of which are hereby incorporated by reference. This patent more specifically includes L-lysine derivatives substituted with N-synthetic amino acids with potent aspartyl protease inhibitory properties. However, it would be beneficial to improve these derivatives by increasing water solubility and bioavailability in order to reduce the burden of pills and make them favorable for patient compliance. It is difficult but interesting to generate active protease inhibitors specifically directed against wild-type and resistant bacteria, so the Stranix et al. Patent known to be active against resistant bacteria Forming derivatives of the original HIV protease inhibitors, such as those described in US Pat. No. 6,632,816, is a viable route with considerable advantages. More specifically, the production of compounds and formulations with high water solubility, oral bioavailability, retention time, and formulation properties, and other advantages is desirable in the development of effective drugs. Therefore, protease inhibitors with improved pharmacokinetics are desirable.

SUMMARY OF THE INVENTION A lysin-based compound with high solubility and improved oral bioavailability is described herein and is filed August 2, 2004, US patent application Ser. No. 10 / 902,935. (Published in February 2006 as 2006 / 0025592A1), the entire contents of which are incorporated herein by reference. These compounds are readily cleaved in vivo to release active ingredients that have an affinity for aspartyl protease and can act as protease inhibitors. More specifically, the active ingredient can bind to, for example, HIV aspartyl protease (US Pat. No. 6,632,816) to inhibit this enzyme. Lysine-based compounds are also referred to herein as protease inhibitor precursors.

  Under in vivo physiological conditions (eg, metabolic, intestinal, and / or gastrointestinal conditions, etc.), lysine-based compounds allow the release of protease inhibitors (eg, aspartyl protease inhibitors). Thus, lysine-based compounds can serve as a means to improve the solubility and / or bioavailability of protease inhibitors, thus reducing the burden of pills and / or reducing the dosage required for inhibition. Can do. The result is improved treatment of HIV-infected patients and can be favorable for patient compliance.

  The compounds described herein can be used to inhibit the activity of cytochrome P450 monooxygenase (CYP450). More specifically, these compounds can be used to inhibit the activity of CYP3A4, including, for example, CYP3A4 / 5.

  Accordingly, the compounds described herein can be used with drugs metabolized by cytochrome P450 monooxygenase to improve their pharmacokinetics. More specifically, these compounds can be used to improve the pharmacokinetics of drugs metabolized by CYP3A4, including CYP3A4 / 5.

  Some drugs that can benefit from inhibition of CYP450 include, for example, the immunosuppressants cyclosporine, FK-506, and rapamycin, the chemotherapeutic agents taxol and taxotere, the antibiotic clarithromycin, and the HIV protease inhibitor A-77003, A-80987, MK-639, VX-478, AG1343, DMP-323, XM-450, BILA2011BS, BILA1096BS, BILA2185BS, BMS186, 318, LB71262, SC-5211, SC-629 (N, N -Dimethylglycyl-N- (2-hydroxy-3-(((4-methoxyphenyl) sulfonyl) (2-methylpropyl) amino) -1- (phenylmethyl) propyl) -3-methyl-L-valinamide) , KNI- 72, CGP53437, CGP57813 and U-103017) may include.

及びその薬学的に許容し得る塩及び誘導体（例えば、本発明の化合物がアミノ基を含む場合、薬学的に許容し得る塩はアンモニウム塩であることができる）を含むことができ、
式中、
ｎは、例えば、３又は４であることができ、
Ｘ及びＹは、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＮＯ_２、−ＮＲ_４Ｒ_５、−ＮＨＣＯＲ_４、−ＯＲ_４、−ＳＲ_４、−ＣＯＯＲ_４、−ＣＯＲ_４、及び−ＣＨ_２ＯＨからなる群から選択することができ、あるいはＸ及びＹは、一緒に、式−ＯＣＨ_２Ｏ−のメチレンジオキシ基及び式−ＯＣＨ_２ＣＨ_２Ｏ−のエチレンジオキシ基からなる群から選択されるアルキレンジオキシ基を定義し、
Ｒ_６は、例えば、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、シクロアルキル部分に３〜６個の炭素原子及びアルキル部分に１〜３個の炭素原子を有するシクロアルキルアルキル基からなる群から選択することができ、
Ｒ_３は、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、及び式Ｒ_３Ａ−ＣＯ−の基からなる群から選択することができ、ここで、Ｒ_３Ａは、例えば、１〜６個の炭素原子の直鎖又は分枝アルキル基（例えば、メチル、エチル−、プロピル、イソ−プロピル、ブチル、イソブチル、ｔｅｒｔ−ブチル、ｔｅｒｔ−ブチル−ＣＨ_２−など）、３〜６個の炭素原子を有するシクロアルキル基（例えば、シクロプロピル−、シクロヘキシル−など）、シクロアルキル部分に３〜６個の炭素原子及びアルキル部分に１〜３個の炭素原子を有するシクロアルキルアルキル基（例えば、シクロプロピル−ＣＨ_２−、シクロヘキシル−ＣＨ_２−、など）、１〜６個の炭素原子のアルキルオキシ基（例えば、ＣＨ_３Ｏ−、ＣＨ_３ＣＨ_２Ｏ−、イソブチルＯ−、ｔｅｒｔ−ブチルＯ−（ＢＯＣ）など）、テトラヒドロ−３−フラニルオキシ、−ＣＨ_２ＯＨ、−ＣＦ_３、−ＣＨ_２ＣＦ_３、−ＣＨ_２ＣＨ_２ＣＦ_３、ピロリジニル、ピペリジニル、４−モルホリニル、ＣＨ_３Ｏ_２Ｃ−、ＣＨ_３Ｏ_２ＣＣＨ_２−、アセチル−ＯＣＨ_２ＣＨ_２−、ＨＯ_２ＣＣＨ_２−、３−ヒドロキシフェニル、４−ヒドロキシフェニル、４−ＣＨ_３ＯＣ_６Ｈ_４ＣＨ_２−、ＣＨ_３ＮＨ−、（ＣＨ_３）_２Ｎ−、（ＣＨ_３ＣＨ_２）_２Ｎ−、（ＣＨ_３ＣＨ_２ＣＨ_２）_２Ｎ−、ＨＯＣＨ_２ＣＨ_２ＮＨ−、ＣＨ_３ＯＣＨ_２Ｏ−、ＣＨ_３ＯＣＨ_２ＣＨ_２Ｏ−、Ｃ_６Ｈ_５ＣＨ_２Ｏ−、２−ピロリル、２−ピリジル、３−ピリジル、４−ピリジル−、２−ピラジニル、２−キノリル、３−キノリル、４−キノリル、１−イソキノリル、３−イソキノリル、２−キノキサリニル、次式のフェニル基、

以下からなる群から選択されるピコリル基、

以下からなる群から選択されるピコリルオキシ基、

以下からなる群から選択される置換ピリジル基、

及び次式の基

からなる群から選択することができ、
Ｘ’及びＹ’は、同じか異なり、例えば、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＦ_３、−ＮＯ_２、−ＮＲ_４Ｒ_５、−ＮＨＣＯＲ_４、−ＯＲ_４、−ＳＲ_４、−ＣＯＯＲ_４、−ＣＯＲ_４、及び−ＣＨ_２ＯＨからなる群から選択することができ、
Ｒ_４及びＲ_５は、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、及び３〜６個の炭素原子のシクロアルキル基からなる群から選択することができ、
Ｒ_２は、式ＩＶのジフェニルメチル基、

式Ｖのナフチル−１−ＣＨ_２−基、

式ＶＩのナフチル−２−ＣＨ_２−基、

式ＶＩＩのビフェニルメチル基、

及び式ＶＩＩＩのアンスリル−９−ＣＨ_２−基、

からなる群から選択することができ、
Ｒ_１は、Ｈ、又は生理的に開裂可能な（physiologically cleavable）単位（該単位によって、（ｉｎ ｖｉｖｏ）生理条件で、前記化合物は、活性なプロテアーゼ阻害剤に変換され得る）であることができる。例えば、生理的に開裂可能な単位の開烈で、これらの化合物は、プロテアーゼ阻害剤を放出し得る。 Exemplary embodiments of compounds that can be used to inhibit CYP450 (eg, CYP3A4) encompassed by the present invention include, for example, compounds of formula I

And pharmaceutically acceptable salts and derivatives thereof (eg, when the compound of the present invention contains an amino group, the pharmaceutically acceptable salt can be an ammonium salt), and
Where
n can be, for example, 3 or 4,
X and Y are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F _{, Cl, Br, I, -CF} 3, -OCF 3, -CN, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4 and, - CH ₂ can be selected from the group consisting of OH, or X and Y, together, the group consisting of the formulas -OCH ₂ O-methylenedioxy group and the formula -OCH ₂ CH ₂ O-ethylenedioxy group Defining an alkylenedioxy group selected from
R ₆ is, for example, a straight chain alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 3 in the alkyl portion. Can be selected from the group consisting of cycloalkylalkyl groups having 1 carbon atom;
R ₃ is H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and the formula R _3A —CO -Can be selected from the group consisting of-groups, wherein _R3A is, for example, a linear or branched alkyl group of 1 to 6 carbon atoms (e.g. methyl, ethyl-, propyl, iso-propyl). , Butyl, isobutyl, tert-butyl, tert-butyl-CH ₂ —, etc.), cycloalkyl groups having 3-6 carbon atoms (eg, cyclopropyl-, cyclohexyl-, etc.), 3-6 in the cycloalkyl moiety pieces cycloalkylalkyl group having 1-3 carbon atoms in the carbon atoms and the alkyl moiety (e.g., cyclopropyl -CH ₂ -, cyclohexyl -CH ₂ -, etc.), 1-6 carbon intensity Alkyl group of the child _{(e.g., CH 3 O-, CH 3 CH} 2 O-, isobutyl O-, tert-butyl O-(BOC), etc.), _{tetrahydro-3-furanyloxy,} -CH 2 OH, _-CF 3, _{-CH 2 CF 3, -CH 2 CH} 2 CF 3, pyrrolidinyl, piperidinyl, _{4-morpholinyl, CH 3 O 2 C-, CH} 3 O 2 CCH 2 -, acetyl _{-OCH 2 CH 2 -, HO 2} CCH 2 - , 3-hydroxyphenyl, _{4-hydroxyphenyl, 4-CH 3 OC 6 H} 4 CH 2 -, CH 3 NH -, (CH 3) 2 N -, (CH 3 CH 2) 2 N -, (CH 3 CH _{2 CH 2) 2 N-, HOCH} 2 CH 2 NH-, CH 3 OCH 2 O-, CH 3 OCH 2 CH 2 O-, C 6 H 5 CH 2 O-, 2- pyrrolyl, - pyridyl, 3-pyridyl, 4-pyridyl -, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of the formula,

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of:

A substituted pyridyl group selected from the group consisting of:

And the group of the following formula

Can be selected from the group consisting of
X ′ and Y ′ are the same or different and are, for example, H, a straight chain alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cyclohexane of 3 to 6 carbon atoms. alkyl _{group, F, Cl, Br, I} , -CF 3, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4, and _-CH 2 OH Can be selected from the group consisting of
R ₄ and R ₅ are the same or different and are H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl of 3 to 6 carbon atoms. Can be selected from the group consisting of groups,
R ₂ is a diphenylmethyl group of formula IV,

Naphthyl of formula V -1-CH ₂ - group,

Naphthyl of the formula VI -2-CH ₂ - group,

A biphenylmethyl group of the formula VII,

And anthryl of formula VIII -9-CH ₂ - group,

Can be selected from the group consisting of
R ₁ can be H, or a physiologically cleavable unit (by which the compound can be converted into an active protease inhibitor under physiological conditions in vivo). . For example, with the opening of a physiologically cleavable unit, these compounds can release protease inhibitors.

According to the present invention, R ₁ can be selected from the group consisting of (HO) ₂ P (O) and (MO) ₂ P (O), where M is an alkali metal (eg, Na, K, Cs Etc.) or alkaline earth metals (Ca, Mg, etc.).

以下からなる群から選択されるピコリル基、

以下からなる群から選択されるピコリルオキシ基、

以下からなる群から選択される置換ピリジル基、

及び次式の基、

からなる群から選択することができ、
Ｘ’、Ｙ’、Ｒ_４、及びＲ_５は、本明細書に定義した通りである。 Further in accordance with the present invention, R ₁ can be a group of formula R _1A —CO—, wherein R _1A is a linear or branched alkyl group of 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, iso - propyl, butyl, isobutyl, tert- butyl, tert- butyl -CH ₂ -, etc.), a cycloalkyl group (e.g., cyclopropyl having 3 to 6 carbon atoms -, cyclohexyl - Etc.), a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 3 carbon atoms in the alkyl moiety (eg, cyclopropyl-CH ₂ —, cyclohexyl-CH ₂ —, etc.), 1 6 alkyl group having a carbon atom _{(e.g., CH 3 O-, CH 3 CH} 2 O-, isobutyl O-, tert-butyl O-(BOC), etc.), - C _{H 2 OH, CH 3 O 2} C-, CH 3 O 2 CCH 2 -, Acetyl _{-OCH 2 CH 2 -, HO 2} CCH 2 -, 2- hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH _{3) 2 NCH 2 -, (} CH 3) 2 CHCH (NH 2) -, HOCH 2 CH 2 NH-, CH 3 OCH 2 O-, CH 3 OCH 2 CH 2 O-, 2- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, A phenyl group of the formula

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of:

A substituted pyridyl group selected from the group consisting of:

And a group of the formula

Can be selected from the group consisting of
X ′, Y ′, R ₄ and R ₅ are as defined herein.

  Accordingly, the compounds referred to herein can be used to improve the pharmacokinetics of drugs in the methods, pharmaceutical compositions, kits, and uses described herein.

式中、
ｎは、３又は４であることができ、
Ｘ及びＹは、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＮＯ_２、−ＮＲ_４Ｒ_５、−ＮＨＣＯＲ_４、−ＯＲ_４、−ＳＲ_４、−ＣＯＯＲ_４、−ＣＯＲ_４、及び−ＣＨ_２ＯＨからなる群から選択することができ、あるいはＸ及びＹは、一緒に、式−ＯＣＨ_２Ｏ−のメチレンジオキシ基及び−ＯＣＨ_２ＣＨ_２Ｏ−のエチレンジオキシ基からなる群から選択することができるアルキレンジオキシ基を定義することができ、
Ｒ_６は、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、シクロアルキル部分に３〜６個の炭素原子を有するシクロアルキルアルキル基、及びアルキル部分に１〜３個の炭素原子からなる群から選択することができ、
Ｒ_３は、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、及び式Ｒ_３Ａ−ＣＯ−の基、からなる群から選択することができ、ここで、Ｒ_３Ａは、１〜６個の炭素原子の直鎖又は分枝アルキル基、３〜６個の炭素原子を有するシクロアルキル基、シクロアルキル部分に３〜６個の炭素原子及びアルキル部分に１〜３個の炭素原子を有するシクロアルキルアルキル基、１〜６個の炭素原子のアルキルオキシ基、テトラヒドロ−３−フラニルオキシ、−ＣＨ_２ＯＨ、−ＣＦ_３、−ＣＨ_２ＣＦ_３、−ＣＨ_２ＣＨ_２ＣＦ_３、ピロリジニル、ピペリジニル、４−モルホリニル、ＣＨ_３Ｏ_２Ｃ−、ＣＨ_３Ｏ_２ＣＣＨ_２−、アセチル−ＯＣＨ_２ＣＨ_２−、ＨＯ_２ＣＣＨ_２−、３−ヒドロキシフェニル、４−ヒドロキシフェニル、４−ＣＨ_３OC_６Ｈ_４ＣＨ_２−、ＣＨ_３ＮＨ−、（ＣＨ_３）_２Ｎ−、（ＣＨ_３ＣＨ_２）_２Ｎ−、（ＣＨ_３ＣＨ_２ＣＨ_２）_２Ｎ−、ＨＯＣＨ_２ＣＨ_２ＮＨ−、ＣＨ_３ＯＣＨ_２Ｏ−、ＣＨ_３ＯＣＨ_２ＣＨ_２Ｏ−、Ｃ_６Ｈ_５ＣＨ_２Ｏ−、２−ピロリル、２−ピリジル、３−ピリジル、４−ピリジル−、２−ピラジニル、２−キノリル、３−キノリル、４−キノリル、１−イソキノリル、３−イソキノリル、２−キノキサリニル、次式のフェニル基、

以下からなる群から選択することができるピコリル基、

以下からなる群から選択することができるピコリルオキシ基、

以下からなる群から選択することができる置換ピリジル基、

及び次式の基

からなる群から選択することができ、
Ｘ’及びＹ’は、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＦ_３、−ＮＯ_２、−ＮＲ_４Ｒ_５、−ＮＨＣＯＲ_４、−ＯＲ_４、−ＳＲ_４、−ＣＯＯＲ_４、−ＣＯＲ_４、及び−ＣＨ_２ＯＨからなる群から選択することができ、
Ｒ_４及びＲ_５は、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、及び３〜６個の炭素原子のシクロアルキル基からなる群から選択することができ、
Ｒ_２は、式ＩＶのジフェニルメチル基、

式Ｖのナフチル−１−ＣＨ_２−基、

式ＶＩのナフチル−２−ＣＨ_２−基

式ＶＩＩのビフェニルメチル基、

及び式ＶＩＩＩのアンスリル−９−ＣＨ_２−基、

からなる群から選択することができ、
Ｈ、又は生理的に開裂可能な単位（該単位によって、（ｉｎ ｖｉｖｏ）生理条件で、前記化合物は、活性なプロテアーゼ阻害剤に変換され得る）であることができる。例えば、生理的に開裂可能な単位の開烈で、当該化合物は、プロテアーゼ阻害剤を放出することができる。 More specifically, the present invention provides:
a) a compound of formula I as described herein or a pharmaceutically acceptable salt thereof,
b) a drug that can be metabolized by cytochrome P450 monooxygenase (eg, CYP3A4);
c) a pharmaceutically acceptable carrier;
Wherein the compound of formula I is represented by:

Where
n can be 3 or 4;
X and Y are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F _{, Cl, Br, I, -CF} 3, -OCF 3, -CN, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4 and, - Can be selected from the group consisting of CH ₂ OH, or X and Y together are from the group consisting of a methylenedioxy group of formula —OCH ₂ O— and an ethylenedioxy group of —OCH ₂ CH ₂ O—. Alkylene dioxy groups that can be selected can be defined,
R ₆ is a straight chain alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl moiety, and alkyl The moiety can be selected from the group consisting of 1 to 3 carbon atoms,
R ₃ is H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and the formula R _3A —CO Wherein R _3A is a linear or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, cycloalkylalkyl groups having 1-3 carbon atoms in the 3 to 6 carbon atoms and the alkyl moiety of the cycloalkyl moiety, 1-6 alkyl group carbon atoms, tetrahydro-3-furanyloxy, -CH _{2 OH, -CF 3, -CH 2 CF} 3, -CH 2 CH 2 CF 3, pyrrolidinyl, piperidinyl, _{4-morpholinyl, CH 3 O 2 C-, CH} 3 O 2 CCH 2 -, acetyl -OCH ₂ CH ₂ - , H ₂ CCH ₂ -, 3- hydroxyphenyl, _{4-hydroxyphenyl, 4-CH 3 OC 6 H} 4 CH 2 -, CH 3 NH -, (CH 3) 2 N -, (CH 3 CH 2) 2 N-, _{(CH 3 CH 2 CH 2)} 2 N-, HOCH 2 CH 2 NH-, CH 3 OCH 2 O-, CH 3 OCH 2 CH 2 O-, C 6 H 5 CH 2 O-, 2- pyrrolyl, 2 Pyridyl, 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group of the formula

A picolyl group, which can be selected from the group consisting of:

A picolyloxy group, which can be selected from the group consisting of:

A substituted pyridyl group that can be selected from the group consisting of:

And the group of the following formula

Can be selected from the group consisting of
X ′ and Y ′ are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms , becomes _{F, Cl, Br, I,} from _{-CF 3, -NO 2, -NR 4} R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4, and _-CH 2 OH You can choose from a group,
R ₄ and R ₅ are the same or different and are H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl of 3 to 6 carbon atoms. Can be selected from the group consisting of groups,
R ₂ is a diphenylmethyl group of formula IV,

Naphthyl of formula V -1-CH ₂ - group,

Naphthyl of the formula VI -2-CH ₂ - group

A biphenylmethyl group of the formula VII,

And anthryl of formula VIII -9-CH ₂ - group,

Can be selected from the group consisting of
H, or a physiologically cleavable unit (by which the compound can be converted to an active protease inhibitor under physiological conditions in vivo). For example, upon opening of a physiologically cleavable unit, the compound can release a protease inhibitor.

以下からなる群から選択されるピコリル基、

以下からなる群から選択されるピコリルオキシ基、

以下からなる群から選択される置換ピリジル基、

及び次式の基、

からなる群から選択することができ、
Ｘ’、Ｙ’、Ｒ_４、及びＲ_５は、本明細書に定義した通りである。 According to the invention, R ₁ is H, (HO) ₂ P (O) and (MO) ₂ P (O) (where M is, for example, an alkali metal or an alkaline earth metal) and the formula R _1A R _1A can be selected from the group consisting of —CO— groups, wherein R _1A is a linear or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms. A cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 3 carbon atoms in the alkyl portion, an alkyloxy group having 1 to 6 carbon atoms, —CH ₂ OH, CH ₃ O _{2 C-, CH 3 O 2 CCH} 2 -, acetyl _{-OCH 2 CH 2 -, HO 2} CCH 2 -, 2- hydroxyphenyl, 3-hydroxyphenyl, _{4-hydroxyphenyl, (CH 3) 2 NCH 2} -, (CH ₃ ) _{2 CHCH (NH 2) -, HOCH} 2 CH 2 NH-, CH 3 OCH 2 O-, CH 3 OCH 2 CH 2 O-, 2- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl - 1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group of the formula

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of:

A substituted pyridyl group selected from the group consisting of:

And a group of the formula

Can be selected from the group consisting of
X ′, Y ′, R ₄ and R ₅ are as defined herein.

によって表され；
式中、
ｎは、３又は４であることができ、
Ｘ及びＹは、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＮＯ_２、−ＮＲ_４Ｒ_５、−ＮＨＣＯＲ_４、−ＯＲ_４、−ＳＲ_４、−ＣＯＯＲ_４、−ＣＯＲ_４、及び−ＣＨ_２ＯＨからなる群から選択することができ、あるいはＸ及びＹは、一緒に、例えば、式−ＯＣＨ_２Ｏ−のメチレンジオキシ基及び式−ＯＣＨ_２ＣＨ_２Ｏ−のエチレンジオキシ基からなる群から選択することができるアルキレンジオキシ基を定義することができ、
Ｒ_６は、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、シクロアルキル部分に３〜６個の炭素原子及びアルキル部分に１〜３個の炭素原子を有するシクロアルキルアルキル基からなる群から選択することができ、
Ｒ_３は、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、及び式Ｒ_３Ａ−ＣＯ−の基からなる群から選択することができ、ここで、Ｒ_３Ａは、１〜６個の炭素原子の直鎖又は分枝アルキル基、３〜６個の炭素原子を有するシクロアルキル基、シクロアルキル部分に３〜６個の炭素原子及びアルキル部分に１〜３個の炭素原子を有するシクロアルキルアルキル基、１〜６個の炭素原子のアルキルオキシ基、テトラヒドロ−３−フラニルオキシ、−ＣＨ_２ＯＨ、−ＣＦ_３、−ＣＨ_２ＣＦ_３、−ＣＨ_２ＣＨ_２ＣＦ_３、ピロリジニル、ピペリジニル、４−モルホリニル、ＣＨ_３Ｏ_２Ｃ−、ＣＨ_３Ｏ_２ＣＣＨ_２−、アセチル−ＯＣＨ_２ＣＨ_２−、ＨＯ_２ＣＣＨ_２−、３−ヒドロキシフェニル、４−ヒドロキシフェニル、４−ＣＨ_３ＯＣ_６Ｈ_４ＣＨ_２−、ＣＨ_３ＮＨ−、（ＣＨ_３）_２Ｎ−、（ＣＨ_３ＣＨ_２）_２Ｎ−、（ＣＨ_３ＣＨ_２ＣＨ_２）_２Ｎ−、ＨＯＣＨ_２ＣＨ_２ＮＨ−、ＣＨ_３ＯＣＨ_２Ｏ−、ＣＨ_３ＯＣＨ_２ＣＨ_２Ｏ−、Ｃ_６Ｈ_５ＣＨ_２Ｏ−、２−ピロリル、２−ピリジル、３−ピリジル、４−ピリジル−、２−ピラジニル、２−キノリル、３−キノリル、４−キノリル、１−イソキノリル、３−イソキノリル、２−キノキサリニル、次式のフェニル基、

以下からなる群から選択することができるピコリル基、

以下からなる群から選択することができるピコリルオキシ基、

以下からなる群から選択することができる置換ピリジル基、

及び次式の基

からなる群から選択することができ、
Ｘ’及びＹ’は、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＦ_３、−ＮＯ_２、−ＮＲ_４Ｒ_５、−ＮＨＣＯＲ_４、−ＯＲ_４、−ＳＲ_４、−ＣＯＯＲ_４、−ＣＯＲ_４、及び−ＣＨ_２ＯＨからなる群から選択することができ、
Ｒ_４及びＲ_５は、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、及び３〜６個の炭素原子のシクロアルキル基からなる群から選択することができ、
Ｒ_２は、式ＩＶのジフェニルメチル基、

式Ｖのナフチル−１−ＣＨ_２−基、

式ＶＩのナフチル−２−ＣＨ_２−基、

式ＶＩＩのビフェニルメチル基、

及び式ＶＩＩＩのアンスリル−９−ＣＨ_２−基

からなる群から選択することができ、
Ｈ、又は生理的に開裂可能な単位（該単位によって、（ｉｎ ｖｉｖｏ）生理条件で、前記化合物は、活性なプロテアーゼ阻害剤に変換され得る）であることができる。 More specifically, the present invention, in one aspect thereof,
a) a compound of formula II and pharmaceutically acceptable salts thereof,
b) a drug that can be metabolized by cytochrome P450 monooxygenase (eg CYP3A4), and c) a pharmaceutically acceptable carrier;
Wherein the compound of formula II is:

Represented by:
Where
n can be 3 or 4;
X and Y are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F _{, Cl, Br, I, -CF} 3, -OCF 3, -CN, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4 and, - CH ₂ OH can be selected from the group consisting of, or X and Y, together, for example, from the formula -OCH ₂ O-methylenedioxy group and the formula -OCH ₂ CH ₂ O- ethylenedioxy group An alkylenedioxy group that can be selected from the group consisting of:
R ₆ is a straight chain alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 3 in the alkyl portion. Can be selected from the group consisting of cycloalkylalkyl groups having carbon atoms;
R ₃ is H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and the formula R _3A —CO Wherein R _3A is a linear or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, cyclo A cycloalkylalkyl group having 3 to 6 carbon atoms in the alkyl moiety and 1 to 3 carbon atoms in the alkyl moiety, an alkyloxy group of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy, —CH ₂ OH _{, -CF 3, -CH 2 CF 3} , -CH 2 CH 2 CF 3, pyrrolidinyl, piperidinyl, _{4-morpholinyl, CH 3 O 2 C-, CH} 3 O 2 CCH 2 -, acetyl -OCH ₂ CH ₂ -, HO CCH ₂ -, 3- hydroxyphenyl, _{4-hydroxyphenyl, 4-CH 3 OC 6 H} 4 CH 2 -, CH 3 NH -, (CH 3) 2 N -, (CH 3 CH 2) 2 N -, ( _{CH 3 CH 2 CH 2) 2} N-, HOCH 2 CH 2 NH-, CH 3 OCH 2 O-, CH 3 OCH 2 CH 2 O-, C 6 H 5 CH 2 O-, 2- pyrrolyl, 2-pyridyl 3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group of the formula

A picolyl group, which can be selected from the group consisting of:

A picolyloxy group, which can be selected from the group consisting of:

A substituted pyridyl group that can be selected from the group consisting of:

And the group of the following formula

Can be selected from the group consisting of
X ′ and Y ′ are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms , becomes _{F, Cl, Br, I,} from _{-CF 3, -NO 2, -NR 4} R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4, and _-CH 2 OH You can choose from a group,
R ₄ and R ₅ are the same or different and are H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl of 3 to 6 carbon atoms. Can be selected from the group consisting of groups,
R ₂ is a diphenylmethyl group of formula IV,

Naphthyl of formula V -1-CH ₂ - group,

Naphthyl of the formula VI -2-CH ₂ - group,

A biphenylmethyl group of the formula VII,

And anthryl of formula VIII -9-CH ₂ - group

Can be selected from the group consisting of
H, or a physiologically cleavable unit (by which the compound can be converted to an active protease inhibitor under physiological conditions in vivo).

以下からなる群から選択することができるピコリル基、

以下からなる群から選択することができるピコリルオキシ基、

以下からなる群から選択することができる置換ピリジル基、

および次式の基

からなる群から選択することができ、
Ｘ’、Ｙ’、Ｒ_４、及びＲ_５は、本明細書に定義した通りである。 According to the invention, R ₁ is H, (HO) ₂ P (O) and (MO) ₂ P (O), where M can be an alkali metal or an alkaline earth metal, And R _1A can be selected from the group consisting of groups of the formula R _1A —CO—, wherein R _1A is a linear or branched alkyl group of 1 to 6 carbon atoms, 3 to 6 carbon atoms a cycloalkyl group having, cycloalkylalkyl group having 1-3 carbon atoms in the 3 to 6 carbon atoms and the alkyl moiety of the cycloalkyl moiety, 1-6 alkyl group carbon atoms, -CH ₂ OH _{, CH 3 O 2 C-, CH} 3 O 2 CCH 2 -, acetyl _{-OCH 2 CH 2 -, HO 2} CCH 2 -, 2- hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, _{(CH 3) 2} NCH _2- , ( _{CH 3) 2 CHCH (NH 2} ) -, HOCH 2 CH 2 NH-, CH 3 OCH 2 O-, CH 3 OCH 2 CH 2 O-, 2- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group of the formula

A picolyl group, which can be selected from the group consisting of:

A picolyloxy group, which can be selected from the group consisting of:

A substituted pyridyl group that can be selected from the group consisting of:

And the group

Can be selected from the group consisting of
X ′, Y ′, R ₄ and R ₅ are as defined herein.

According to an embodiment of the present invention, there is provided herein a pharmaceutical composition comprising a compound of formula II, wherein R ₆ can be, for example, isobutyl and n can be 3. Is included.

According to an additional embodiment of the present invention, the pharmaceutical composition comprising a compound of formula II, wherein R ₆ can be, for example, isobutyl and n can be 4, Included in the specification.

In certain embodiments of the invention, R ₁ can be selected from the group consisting of H, (HO) ₂ P (O), and (NaO) ₂ P (O).

In another specific embodiment of the invention, R ₁ is from a group consisting of CH ₃ CO, 3-pyridyl-CO, (CH ₃ ) ₂ NCH ₂ CO, and (CH ₃ ) ₂ CHCH (NH ₂ ) CO. You can choose.

According to another particular embodiment of the invention, a compound of formula II wherein R ₃ is CH ₃ CO, CH ₃ O—CO, (CH ₃ ) ₂ N—CO, 3-pyridyl-CO, A pharmaceutical composition comprising 4-pyridyl-CO and a group consisting of 4-morpholine-CO) is encompassed by the present invention.

According to an embodiment of the present invention, X can be 4-NH ₂ and Y can be H or F.

  According to an embodiment of the present invention, both X ′ and Y ′ can be H.

According to a particular embodiment of the invention, a compound of formula II wherein R ₂ is a diphenylmethyl group of formula IV, a naphthyl-1-CH ₂ group of formula V, a naphthyl-2-CH of formula VI ₂ - group, a biphenyl methyl group of the formula VII, and anthryl -9-CH 2 of formula VIII _- may be selected from the consisting of group group) pharmaceutical compositions comprising a are encompassed herein.

For example, _{R 2,} more specifically, diphenylmethyl group of Formula IV, naphthyl of formula V -1-CH ₂ - group, and naphthyl -2-CH ₂ of formula VI - be selected from the group consisting of group Can do.

In a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula II, wherein R ₆ is isobutyl, n is 4, and R ₂ is a diphenylmethyl group of formula IV. provide.

According to an embodiment of the present invention, R ₁ can be selected from the group consisting of H, (HO) ₂ P (O) and (NaO) ₂ P (O).

According to a further embodiment of the invention, R ₁ is selected from the group consisting of CH ₃ CO, 3-pyridyl-CO, (CH ₃ ) ₂ NCH ₂ CO, and (CH ₃ ) ₂ CHCH (NH ₂ ) CO. can do.

According to an additional embodiment of the invention, R ₃ is CH ₃ CO, CH ₃ O—CO, (CH ₃ ) ₂ N—CO, 3-pyridyl-CO, 4-pyridyl-CO, and 4-morpholine. It can be selected from the group consisting of —CO.

According to an embodiment of the present invention, X can be 4-NH ₂ and Y can be H or F.

More specifically, according to an embodiment of the present invention, the present invention provides a compound of formula II wherein X can be, for example, 4-NH ₂ and Y is H. Wherein X ′ can be H, Y ′ can be H, and R ₃ can be CH ₃ O—CO). .

According to a particular embodiment of the invention, R ₁ can be (HO) ₂ P (O).

According to another particular embodiment of the invention, R ₁ can be (NaO) ₂ P (O).

According to a further specific embodiment of the invention, R ₁ can be H.

More specifically, according to a further embodiment of the present invention, the present invention provides compounds of formula II wherein X can be 4-NH ₂ and Y is 3-F And X ′ can be H, Y ′ can be H, and R ₃ can be CH ₃ O—CO). To do.

According to a particular embodiment of the invention, R ₁ can be (HO) ₂ P (O).

According to another particular embodiment of the invention, R ₁ can be (NaO) ₂ P (O).

According to a further particular embodiment of the invention, R ₁ can be H.

More specifically, according to an additional embodiment of the present invention, the present invention provides a compound of formula II wherein X is 4-NH ₂ and Y is H or 3-F; Wherein X ′ is H, Y ′ is H and R ₃ is CH ₃ CO).

According to a particular embodiment of the invention, R ₁ can be (HO) ₂ P (O).

According to another particular embodiment of the invention, R ₁ can be (NaO) ₂ P (O).

According to a further specific embodiment of the invention, R ₁ can be H.

More specifically, according to an embodiment of the present invention, the present invention further provides a compound of formula II wherein X is 4-NH ₂ and Y is H or 3-F, X 'Is H, Y' is H and R ₃ is 4-morpholine-CO).

According to an embodiment of the present invention, X can be 4-NH ₂ , Y can be H, X ′ can be H, and Y ′ is H. And R ₃ can be CH ₃ O—CO.

According to a particular embodiment of the invention, R ₁ can be 3-pyridyl-CO.

According to another particular embodiment of the invention, R ₁ can be (CH ₃ ) ₂ NCH ₂ CO.

According to yet another specific embodiment of the invention, R ₁ can be (CH ₃ ) ₂ CHCH (NH ₂ ) CO.

According to additional specific embodiments of the present invention, R ₁ can be CH ₃ CO.

In an additional embodiment, the invention provides a compound of formula II wherein R ₆ is isobutyl, n is 4, X ′ and Y ′ are both H, and R ₂ is naphthyl -1-CH ₂ - and is, X is 4-NH _2, Y is H, _{R 3} is 4-morpholine -CO, _{R 1} is, H, _(HO) 2 P (O) and (NaO) ₂ P (O) can be selected).

In a further embodiment, the present invention provides a compound of formula II wherein R ₆ is isobutyl, n is 4, X ′ and Y ′ are both H, and R ₂ is naphthyl. -2-CH ₂ - and is, X is 4-NH _2, Y is H, _{R 3 is} CH 3 O-CO, _{R 1 is, H, (HO) 2 P} ( O), and (NaO) ₂ P (O) can be selected).

及びその薬学的に許容し得る塩、
Ｘ及びＹは、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＮＯ_２、−ＮＲ_４Ｒ_５、−ＮＨＣＯＲ_４、−ＯＲ_４、−ＳＲ_４、−ＣＯＯＲ_４、−ＣＯＲ_４、及び−ＣＨ_２ＯＨからなる群から選択することができ、あるいはＸ及びＹは、一緒に、式−ＯＣＨ_２Ｏ−のメチレンジオキシ基及び式−ＯＣＨ_２ＣＨ_２Ｏのエチレンジオキシ基からなる群から選択されるアルキレンジオキシ基を定義し、
Ｘ’及びＹ’は、同じか異なり、Ｈ、１〜６個の炭素原子の直鎖アルキル基、３〜６個の炭素原子の分枝アルキル基、３〜６個の炭素原子のシクロアルキル基、Ｆ、Ｃｌ、Ｂｒ、Ｉ、−ＣＦ_３、−ＮＯ_２、−ＮＲ_４Ｒ_５、−ＮＨＣＯＲ_４、−ＯＲ_４、−ＳＲ_４、−ＣＯＯＲ_４、−ＣＯＲ_４及び−ＣＨ_２ＯＨからなる群から選択することができ、
ｎ、Ｒ_１、Ｒ_３、Ｒ_４、Ｒ_５、及びＲ_６は、本明細書に定義した通りである；
ｂ）シトクロムＰ４５０モノオキシゲナーゼによって代謝され得る薬物、及び；
ｃ）薬学的に許容し得る担体
を含むことができる医薬組成物を提供する。 More specifically, the present invention provides:
a) Compound of formula IIa

And pharmaceutically acceptable salts thereof,
X and Y are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F _{, Cl, Br, I, -CF} 3, -OCF 3, -CN, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4 and, - can be selected from the group consisting of CH ₂ OH, or X and Y, together, from the group consisting of ethylenedioxy group methylenedioxy group of formula -OCH ₂ O-and formula -OCH ₂ CH ₂ O Define the alkylenedioxy group selected,
X ′ and Y ′ are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms _{, F, Cl, Br, I} , -CF 3, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, the group consisting of -COR ₄ and _-CH 2 OH You can choose from
n, R ₁ , R ₃ , R ₄ , R _5, and R ₆ are as defined herein;
b) a drug that can be metabolized by cytochrome P450 monooxygenase, and;
c) Provide a pharmaceutical composition that can include a pharmaceutically acceptable carrier.

以下からなる群から選択されるピコリル基、

以下からなる群から選択されるピコリルオキシ基、

以下からなる群から選択される置換ピリジル基、

及び次式の基

からなる群から選択することができ、
Ｘ’、Ｙ’、Ｒ_４、及びＲ_５は、本明細書に定義した通りである。 According to an embodiment of the present invention, R ₁ is H, (HO) ₂ P (O) and (MO) ₂ P (O), where M is an alkali metal or alkaline earth metal, And a group of formula R _1A —CO—, wherein R _1A is a straight or branched alkyl group of 1 to 6 carbon atoms, 3 to 6 in the cycloalkyl moiety. A cycloalkylalkyl group having 1 to 3 carbon atoms in the carbon atom and the alkyl moiety, an alkyloxy group having 1 to 6 carbon atoms, —CH ₂ OH, CH ₃ O ₂ C—, CH ₃ O ₂ CCH ₂ - acetyl -OCH ₂ CH _{2 -,} HO 2 _CCH 2 -, 2-hydroxyphenyl, 3-hydroxyphenyl, _{4-hydroxyphenyl, (CH 3) 2 NCH 2} -, (CH 3) 2 CHCH (NH 2 ) -, HOCH _{CH 2 NH-, CH 3 OCH 2} O-, CH 3 OCH 2 CH 2 O-, 2- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group of the formula

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of:

A substituted pyridyl group selected from the group consisting of:

And the group of the following formula

Can be selected from the group consisting of
X ′, Y ′, R ₄ and R ₅ are as defined herein.

According to another embodiment of the present invention, R ₆ can be isobutyl.

  According to yet another embodiment of the present invention, n can be 4.

According to a further embodiment of the invention, R ₁ can be selected from the group consisting of H, (HO) ₂ P (O), and (NaO) ₂ P (O).

According to a further embodiment of the invention, R ₁ is selected from the group consisting of CH ₃ CO, 3-pyridyl-CO, (CH ₃ ) ₂ NCH ₂ CO, and (CH ₃ ) ₂ CHCH (NH ₂ ) CO. can do.

According to a further embodiment of the invention, R ₃ is CH ₃ CO, CH ₃ O—CO, (CH ₃ ) ₂ N—CO, 3-pyridyl-CO, 4-pyridyl-CO, and 4-morpholine— It can be selected from the group consisting of CO.

According to another embodiment of the invention, R ₃ is CH ₃ CO, CH ₃ O—CO, (CH ₃ ) ₂ N—CO, 3-pyridyl-CO, 4-pyridyl-CO, and 4-morpholine. Can be selected from the group consisting of -CO

According to an embodiment of the present invention, X can be 4-NH ₂ and Y can be H or F.

According to another embodiment of the present invention, X can be 4-NH ₂ and Y can be H or F.

According to a further embodiment of the invention, X can be 4-NH ₂ , Y can be H or 3-F, X ′ can be H, Y ′ Can be H and R ₃ can be CH ₃ CO.

According to another embodiment of the present invention, X can be a 4-NH _2, Y may be H or 3-F, X 'may be H, Y 'Can be H and R ₃ can be 4-morpholine-CO.

According to certain embodiments of the invention, X can be 4-NH ₂ , Y can be H, X ′ can be H, Y ′ can be H R ₃ can be CH ₃ O—CO and R ₁ can be (HO) ₂ P (O), (NaO) ₂ P (O), or H. .

According to another particular embodiment of the invention, X can be 4-NH ₂ , Y can be 3-F, X ′ can be H, Y 'Can be H, R ₃ can be CH ₃ O—CO, and R ₁ can be (HO) ₂ P (O), (NaO) ₂ P (O), or H Can be.

According to a further particular embodiment of the invention, X can be 4-NH ₂ , Y can be H or 3-F, X ′ can be H, Y ′ can be H, R ₃ can be CH ₃ CO, and R ₁ is (HO) ₂ P (O), (NaO) ₂ P (O), or H be able to.

According to another particular embodiment of the invention, X can be 4-NH ₂ , Y can be H or 3-F, and X ′ can be H. , Y ′ can be H and R ₃ can be 4-morpholine-CO.

According to additional embodiments of the present invention, X can be 4-NH ₂ , Y can be H, X ′ can be H, Y ′ can be H R ₃ can be CH ₃ O—CO and R ₁ is 3-pyridyl-CO, (CH ₃ ) ₂ NCH ₂ CO, (CH ₃ ) ₂ CHCH (NH ₂ ) It can be CO or CH ₃ CO.

According to another embodiment of the present invention, X can be 4-NH ₂ , Y can be 3-F, X ′ can be H, Y ′ can be , H, R ₃ can be CH ₃ O—CO, and R ₁ can be 3-pyridyl-CO, (CH ₃ ) ₂ NCH ₂ CO, or (CH ₃ ) ₂ CHCH ( It can be NH ₂ ) CO.

（式中、Ｙ、ｎ、Ｒ_１、Ｒ_２、Ｒ_３、Ｘ’、及びＹ’は、本明細書に定義した通りである。 Other compounds that can be used to practice the invention can include, for example, a compound of formula IIA;

Wherein Y, n, R ₁ , R ₂ , R ₃ , X ′, and Y ′ are as defined in this specification.

According to the invention, R ₁ can be, for example, H, (HO) ₂ P (O), or (NaO) ₂ P (O). Further in accordance with the present invention, n can be 4. Y can be, for example, H. R ₃ can be, for example, CH ₃ O—CO. R ₂ can be, for example, a diphenylmethyl group of formula IV, where X ′ and Y ′ can be, for example, H.

例えば、式ＩＩＡ’の化合物（式中、Ｒ_１は、Ｈまたは（ＨＯ）_２Ｐ（Ｏ）である）又は式ＩＩＡ’の化合物（式中、Ｒ_１が（ＮａＯ）_２Ｐ（Ｏ）である）などである。 Compounds of formula IIA ′ and pharmaceutically acceptable salts and derivatives thereof can be used to practice the invention,

For example, a compound of formula IIA ′ where R ₁ is H or (HO) ₂ P (O) or a compound of formula IIA ′ where R ₁ is (NaO) ₂ P (O) Etc.).

For example, the pharmaceutical compositions, methods, uses, and kits encompassed by the present invention can include one or more of the following compounds and combinations thereof;
A compound of formula IIa, wherein n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is H and X ′ is H Y ′ is H, R ₆ is isobutyl, R ₃ is CH ₃ O—CO,
A compound of formula IIa, wherein n is 4, R ₁ is (NaO) ₂ P (O), X is 4-NH ₂ , Y is H and X ′ is H Y ′ is H, R ₆ is isobutyl, R ₃ is CH ₃ O—CO,
A compound of formula IIa, wherein n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is H and X ′ is H Y ′ is H, R ₆ is isobutyl, R ₃ is CH ₃ CO,
A compound of formula IIa, wherein n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is 3-F, and X ′ is H Y ′ is H, R ₆ is isobutyl and R ₃ is CH ₃ O—CO.
A compound of formula IIa, wherein n is 4, R ₁ is CH ₃ CO, X is 4-NH ₂ , Y is H, X ′ is H, Y ′ is H R ₆ is isobutyl and R ₃ is CH ₃ O—CO,
A compound of formula IIa, wherein n is 4, R ₁ is 3-pyridyl-CO, X is 4-NH ₂ , Y is H, X ′ is H, Y ′ Is H, R ₆ is isobutyl, R ₃ is CH ₃ O—CO,
A compound of formula IIa, wherein n is 4, R ₁ is (CH ₃ ) ₂ NCH ₂ CO, X is 4-NH ₂ , Y is H and X ′ is H Y ′ is H, R ₆ is isobutyl, R ₃ is CH ₃ O—CO,
A compound of formula IIa, wherein n is 4, R ₁ is (CH ₃ ) ₂ CHCH (NH ₂ ) CO, X is 4-NH ₂ , Y is H and X ′ is H, Y ′ is H, R ₆ is isobutyl, R ₃ is CH ₃ O—CO,
A compound of formula IIb, wherein n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is H and X ′ is H Y ′ is H, R ₆ is isobutyl, R ₃ is CH ₃ O—CO, and the naphthyl group is a naphthyl-2-CH ₂ group,
A compound of formula IIb, wherein n is 4, R ₁ is (HO) ₂ P (O), X is 4-NH ₂ , Y is H and X ′ is H Y ′ is H, R ₆ is isobutyl, R ₃ is 4-morpholine-CO, the naphthyl group is a naphthyl-1-CH ₂ group, or any combination of the above compounds.

Any compound that is a precursor of an active ingredient described herein can be used to practice the invention and is encompassed by the invention. For example, compounds that can release or produce an active ingredient of the following formula (either in vivo or in vitro) are encompassed by the present invention.

  The identified active ingredient is identified herein as PL-100, and any precursor capable of releasing or producing the representative compound described above either in vivo or in vitro is It is understood herein that the methods, pharmaceutical compositions, kits, and uses encompassed by the invention and described herein can be used to practice.

In addition, compounds that release an active ingredient of the following formula (either in vivo or in vitro) can be used to practice the invention and are therefore encompassed by the invention.

  The identified active ingredient is identified herein as PL-337, and any precursor capable of releasing or producing the representative compound described above either in vivo or in vitro is: It will be understood herein that it can be used to practice the invention and is encompassed by the invention.

  Accordingly, the present invention relates to the use of the compounds described herein for improving the pharmacokinetics of a drug that may be affected by CYP450, more specifically CYP3A4 (eg, CYP3A4 / 5, etc.). About.

  The present invention provides administration of a compound described herein to an individual in need thereof with one or more drugs that can be acted upon (metabolized) by CYP450, more specifically CYP3A4 (eg, CYP3A4 / 5, etc.). It also relates to a method of treatment that may comprise. As indicated herein, administration can occur simultaneously or at different time intervals. The compound and drug may or may not be mixed together.

  The invention further uses the compounds described herein in the manufacture of a medicament for improving the pharmacokinetics of a drug that can be acted upon by CYP450, more specifically CYP3A4 (eg, CYP3A4 / 5, etc.). About.

  The invention further relates to the use of a compound as described herein and a drug capable of being acted upon by CYP450 in the manufacture of a medicament for treating a patient in need thereof.

  The term “pharmaceutically effective amount” refers to an amount effective to treat, prevent or reduce the risk or potential of HIV infection, or an amount effective to reduce the burden of HIV.

  The term “pharmaceutically effective amount” refers to the treatment, prevention, or risk of developing acquired immune deficiency syndrome (AIDS) to delay the onset of AIDS or to reduce the symptoms of AIDS, or The amount effective for reduction is also referred to. "Pharmaceutically effective amount" as used herein is taken in a single dose or multiple doses, taken by any dose or route, or taken alone or in combination with other therapeutic agents. It is also understood that it may be understood as an amount that provides the desired therapeutic effect. In the present case, a “pharmaceutically effective amount” is HIV (HIV-1 and HIV-2 and related viruses such as HTLV-I and HTLV-II, and Simian immunodeficiency virus (SIV)). ) Amounts that have an inhibitory effect (partially or fully) on the infection cycle (eg, replication, reinfection, maturation, inhibition of budding, etc.) and any organism that depends on aspartyl protease for its life cycle It may be understood as an amount having an inhibitory effect (partially or entirely). An inhibitory effect is used herein to refer to the effect of reducing the ability of an organism (eg, HIV) to reproduce (replicate) itself, the ability to re-infect surrounding cells, or complete inhibition of an organism ( (Or exclusion).

  The terms “HIV protease” and “HIV aspartyl protease” are used interchangeably and include, for example, aspartyl protease encoded by human immunodeficiency virus type 1 or type 2.

  The terms “pharmaceutically acceptable carrier”, “pharmaceutically acceptable adjuvant”, and “physiologically acceptable vehicle” are administered to a patient together with one or more compounds of the present invention. A non-toxic carrier or adjuvant that can be produced and does not impair its pharmacological activity.

  The term “precursor” refers to a compound such as a lysine-based compound that can be converted into an active component in vitro or in vivo. For example, because PL-461 is converted to PL-100 in vivo (eg, under physiological conditions) when administered to an individual, compound PL-461 is a precursor to compound PL-100.

  The term “derivative” refers to a compound that is chemically synthesized from the original compound. For example, considering the synthetic synthesis of PL-461, PL-461 is a derivative of PL-100.

  The term “consisting essentially of” means that a pharmaceutical composition includes a specific substance and other substances that do not materially change the basic characteristics of the pharmaceutical composition. It means that it may be included.

  Pharmaceutically acceptable derivatives of compounds of formula I (such as compounds of formulas I, II, IIa, IIb, IIc, IIA, and IIA ′) and, where applicable, their pharmaceutically acceptable salts ( For example, ammonium salts) are described herein. A “pharmaceutically acceptable derivative” is capable of providing (directly or indirectly) an active compound or antiviral active metabolite or residue thereof when administered to a recipient (mammal). It means any pharmaceutically acceptable salt, ester, or salt of such an ester of a compound of the present invention or any other compound.

  It is understood herein that “a linear alkyl group of 1 to 6 carbon atoms” includes, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl.

  As used herein, “branched alkyl groups of 3 to 6 carbon atoms” are understood herein to include, for example, without limitation, isobutyl, tert-butyl, 2-pentyl, 3-pentyl, and the like. .

“Cycloalkyl having 3 to 6 carbon atoms” includes, but is not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (ie, C ₆ H ₁₁ ). I understand.

Salts derived from appropriate bases include alkali metal (eg, sodium), alkaline earth metal (eg, magnesium), ammonium, and N ⁻ (C _1-4 alkyl) ₄ ⁺ salts.

  The compounds described herein contain one or more asymmetric carbon atoms and can exist as racemates and racemic mixtures and as individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon can be in the R or S configuration.

  Pharmaceutically acceptable salts of the compounds described herein include those derived from pharmaceutically acceptable inorganic and / or organic acids or bases. Examples of such acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfone Acid salt, cyclopentanepropionate, digluconate, dodecyl hydrogensulfate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, Hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate , 2-naphthyl sulfonate, nicotinate, nitrate, oxalate, pamoate, pectate, perchlorate, persulfate, 3-phenylpropionate, phosphate Picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate (tosylate), and include undecanoate.

  The compounds encompassed by the present invention also contemplate quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Basic nitrogen includes, for example, lower alkyl halides (such as ethyl, propyl, and butyl chlorides, bromides, and iodides); dialkyl sulfates (including dimethylmethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate); Any known to those skilled in the art, including long chain halides (such as decyl, lauryl, myristyl, and stearyl chloride, bromide, and iodide), and aralkyl halides (including benzyl bromide and phenethyl bromide) Can be quaternized with these agents. Water or oil soluble or dispersible products can be obtained by such quaternization.

Where “range” or “substance” is referred to with respect to a particular feature of the present invention (eg, temperature, concentration, time, etc.), the present invention includes each and every particular member, and what is included Anyway, it is understood here that it relates to a combination of sub-ranges or subgroups, which are expressly incorporated herein. Thus, any specified range or group is a shorthand way of indicating each and every member individually and all and all possible subranges or subgroups included with respect to the range or group. It is understood that the same is true for any sub-range or subgroup. So, for example,
-With respect to the number of carbon atoms, references to the range of 1 to 6 carbon atoms are used herein for each and every individual number of carbon atoms, as well as, for example, 1 carbon atom, 3 carbon atoms. Understood to incorporate subranges such as 4-6 carbon atoms,
-With respect to the reaction time, 1 minute or more is for each and every individual time, and in the partial ranges above 1 minute, for example 1 minute, 3-15 minutes, 1 minute-20 hours, 1-3 hours 16 hours, 3 hours to 20 hours, etc. are specifically incorporated herein,
Similarly, the same applies to other parameters such as concentration and composition.

  Each compound formula includes each and every individual compound described thereby, as well as each and every possible class or subgroup or subclass of compounds (such classes or subclasses include a particular compound, Are specifically understood herein, whether or not positively defined as excluding certain compounds or combinations thereof, for example, excluding definitions for formula (eg, I) include the following: Can be read as follows: “However, when one of A and B is —COOH and the other is H, —COOH cannot occupy the 4 ′ position”.

  It is understood that “g” or “gm” refers herein to gram weight units and “C” or “° C.” refers to temperature units.

  The compounds described herein can be prepared from readily available starting materials using conventional techniques. Detailed descriptions of these techniques are provided, for example, in Schemes 1-5 below.

  Scheme 1 illustrates a general example of the preparation of a phosphate monoester III derived from a primary alcohol (see I), a compound of an HIV protease inhibitor (herein described for a specific example of this synthesis). Example 1 (see steps G and H) in the experimental part).

Note: a) R ₂ and R ₃ are as defined herein.

  Synthesis of phosphate monoester III can use an HIV aspartyl protease inhibitor (I, see US Pat. No. 6,632,816) as a starting material. Diethylphosphotriester II was obtained in good yield when treated with diethyl chlorophosphate and sodium hydride in a mixture of tetrahydrofuran and triethyl phosphate. Compound III was then obtained in good to excellent yields by adding trimethylsilyl chloride in dichloromethane (DCM).

  Scheme 1A represents another general example for the preparation of phosphate monoester IIIA derived from a primary alcohol (see IA), a compound of an HIV protease inhibitor.

Note: a) n, X, Y, R ₂ , R ₃ , and R ₆ are as defined herein.

  Synthesis of phosphate monoester IIIA is performed as described for the preparation of III (Scheme 1).

  Scheme 2 illustrates a general example of the preparation of phosphate monoester III, a compound of an HIV protease inhibitor, using a different approach starting from (3S) -3-isobutylamino-azepan-2-one (IV). To do.

Note: a) R ₂ and R ₃ are as defined herein.

  As shown in Scheme 2, the phosphate monoester derivative III was obtained from (3S) -3-isobutylamino-azepan-2-one (IV) in a seven step reaction sequence. First, (2S) -3-isobutylamino-azepan-2-one (IV) is sulfonated with 4-acetamidobenzenesulfonyl chloride in the presence of triethylamine in dichloromethane to obtain compound V in excellent yield. It was. Derivative VI was obtained quantitatively when V was treated with di-tert-butyl pyrocarbonate and DMAP in acetonitrile. Reductive ring opening with sodium borohydride in ethanol produced the key intermediate VII in good yield. Diethyl phosphotriester VIII was obtained in good yield when treated with diethyl chlorophosphate and sodium hydride in a mixture of tetrahydrofuran and triethyl phosphate. The BOC protecting group was removed by treatment with HCl in ethanol to give compound IX quantitatively ((TW Greene and PMGM Wuts, Protective groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999), then present on intermediate IX in the presence of 1-hydroxybenzotriazole (HOBt) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDAC) The coupling of the free amino group to various synthetic amino acids yielded derivatives II in good to excellent yields, and finally compound III was improved by the addition of trimethylsilyl bromide in dichloromethane (DCM). It was obtained in an excellent yield.

  Scheme 3 shows a diphenylmethyl derivative; (1S, 5S)-(1- {5-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6-hydroxy-hexylcarbamoyl} -2,2-diphenyl-ethyl ) -Carbamic acid methyl ester (PL-100) is converted to its fluorophosphate monoester sodium salt analog XI. This reaction sequence can be used to produce compounds formed with unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl, and 9-anthryl groups as described herein.

  Therefore, treatment of PL-100 with Selectfluor® in acetonitrile gave derivative X in 38% yield. Introduction of the phosphoric acid monoester group was performed as described in Schemes 1 and 2 above. First, the diethylphosphotriester intermediate could be obtained in good yield when treated with diethyl chlorophosphate and sodium hydride in a mixture of tetrahydrofuran and triethyl phosphate. Second, the addition of trimethylsilyl bromide in dichloromethane (DCM) gave the phosphate monoester compound in good to excellent yields. Treatment of the phosphate monoester with a solution of sodium hydroxide provided the final product XI easily in good yield.

  Scheme 4 illustrates a general example for converting phosphotriester II to its fluorinated analog XIII in a two step reaction sequence. This general example represents a second approach for the synthesis of the fluorinated compounds described herein. In this case, as shown in Scheme 3, a fluorine atom is added to the phosphotriester II instead of the primary alcohol derivative of general formula I, more specifically instead of PL-100. Using this alternative reaction sequence, any other similar compound formed with the unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl, and 9-anthryl groups described herein. Can be generated.

Note: a) R ₂ and R ₃ are as defined herein.

  Briefly, derivative XII was obtained in good yield by treating derivative II with Selectfluor® in acetonitrile. The addition of trimethylsilyl bromide in dichloromethane (DCM) then gave the phosphoric acid monoester compound XIII in good to excellent yields. If desired, the final product XIII can be readily converted to a phosphate monoester sodium salt analog as in Scheme 3 above.

Scheme 5 illustrates a representative synthesis of the various ester compounds XVI described herein. Ester compounds are known to be readily cleaved in vivo by esterase enzymes and as a result can release active ingredients. In this scheme, R ₂ is defined as a diphenylmethyl group. However, using this reaction sequence, any other similar compound formed with the unsubstituted (or substituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl, and 9-anthryl groups described herein. Can be generated.

Note: a) R _1A represents the “residue” of the acid molecule attached to the free primary alcohol group present on intermediate XV, as defined herein.

  The compound XVI is generally obtained in high yield in a three-step reaction sequence. (1S)-{4-[(5-tert-butoxycarbonyl) in the presence of 1-hydroxybenzotriazole (HOBt) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDAC) Esterification of amino-1-hydroxymethyl-pentyl) -isobutyl-sulfamoyl] -phenyl} -carbamic acid tert-butyl ester (VII) with various acids provides the desired ester XIV in excellent yield. The acetyl ester was obtained quantitatively using acetic anhydride in the presence of N, N-dimethylaminopyridine (DMAP) in dichloromethane (DCM). Treatment with trifluoroacetic acid (TFA) in DCM quantitatively achieved BOC protecting group cleavage. A second coupling with (2S) -2-methoxycarbonylamino-3,3-diphenyl-propionic acid is carried out on the primary amino group of intermediate XV with HOBt and EDAC to give the desired compound XVI. Can be obtained in good to excellent yields. If necessary, catalytic hydrogenation of the benzyloxycarbonyl group with 10% palladium on charcoal yields the final compound XVII.

  As will be appreciated by those skilled in the art, the above synthetic schemes, which can be used to synthesize the compounds described herein, but are only given as examples of a number of synthetic methods, are a comprehensive listing of all means. Not intended to be. Further, the method will be apparent to those skilled in the art.

  The compounds described herein may be modified with additional suitable functionalities to enhance selective biological properties. Such modifications include those that increase biological penetration into a given biological system (eg, blood, lymphatic system, central nervous system), those that increase oral availability, and injections that increase solubility. Those that allow administration, those that change metabolism, and those that change the excretion rate are included.

  The pharmaceutical composition of the present invention includes any of the compounds of the present invention and pharmaceutically acceptable salts thereof together with any pharmaceutically acceptable carrier, adjuvant, or vehicle. Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lectins, serum proteins, such as Human serum albumin, buffer substances such as phosphate buffer, glycine, sorbic acid, calcium sorbate, partial glyceride mixtures of saturated plant fatty acids, water, salts, or electrolytes such as protamine sulfate, dihydrogen phosphate Sodium, calcium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-poly Carboxymethyl propylene - block polymers, polyethylene glycol, and a wool fat.

  Accordingly, it is understood herein that oral administration or administration by injection is encompassed by the present invention. For example, the compounds of the present invention can be administered orally, for example, in an aqueous solution. The pharmaceutical compositions of the present invention may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle. The term “parenteral” as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, And intracranial injection or infusion techniques.

  When the compounds described herein are administered in combination with drugs that can be metabolized by CYP450, they may be administered to the patient sequentially or simultaneously. Administration of the compound and drug can also be separated by a suitable time interval.

The following abbreviations are used in the detailed description herein:
Abbreviation Meaning
Ac Acetyl
AcOH acetic acid
APCI atmospheric pressure chemical ionization
AIDS acquired immune deficiency syndrome
APV Amprenavir
ATV Atazanavir
AZT 3-azido-3-deoxythymine (Zidovudine)
BOC benzyloxycarbonyl
t-butyl tert-butyl
CAM Cerium ammonium molybdate
DCM dichloromethane
DMAP N, N-dimethylaminopyridine
DMSO Dimethyl sulfoxide
DMF Dimethylformamide
DNA deoxyribonucleic acid
EDAC 1- [3- (Dimethylamino) propyl] -3-ethyl
Carbodiimide hydrochloride
EtOAc ethyl acetate
EtOH ethyl alcohol
g grams
h hours
HIV-1, -2 human immunodeficiency virus type 1 and 2
HOBt 1-hydroxybenzotriazole
HPLC high performance liquid chromatography
HTLV-I, -II Human T-cell leukemia virus type I, type II
IL-2 Interleukin-2
IDV Indinavir
Kg Kilogram
L liter
LC-MS liquid chromatography-mass spectrometry
LPV Lopinavir
M mole
MeOH methyl alcohol
mg milligrams
mp melting point
min minutes
Moc Methoxycarbonyl
mol mol
mL milliliter
mmol
NFV Nelfinavir
nm nanometer
nM nanomolar
po oral
rEPO recombinant erythropoietin
RTV Ritonavir
SQV Saquinavir
TLC thin layer chromatography
3TC 2 ', 3'-dideoxy-3-thiacytidine
TFA trifluoroacetic acid
THF tetrahydrofuran

Examples This section describes the synthesis of lysine-based compounds that can release the HIV aspartyl protease inhibitors described herein. These examples are for illustrative purposes and are in no way to be understood as limiting the scope of the invention. This section provides a detailed synthesis of compounds Nos. 1-10 of the present invention.

  A representative synthetic scheme for the active ingredient is disclosed in US Pat. No. 6,632,816 to Stranix et al.

Materials and Methods—Preparation of Compounds Analytical thin layer chromatography (TLC) was purified on 0.25 mm silica gel E. coli. Performed using Merck 60F ₂₅₄ plates and eluted with the indicated solvent system. Preparative chromatography was performed by flash chromatography using silica gel 60 (EM Science) with the indicated solvent system and positive air pressure allowing the appropriate elution rate. Compound detection involves exposing the eluted plate (analytical or preparative) to iodine, UV light, and / or the analytical plate of p-anisaldehyde in ethanol containing 3% sulfuric acid and 1% acetic acid. This was done by treating with a 2% solution followed by heating. Alternatively, the analytical plate can be prepared by adding 20 g of (NH ₄ ) ₆ Mo ₇ O ₂₄ in water (750 mL) containing a 0.3% ninhydrin solution in ethanol containing 3% acetic acid and / or concentrated sulfuric acid (90 mL). And 8.3 g Ce (SO ₄ ) ₂ polyhydrate (Ce (SO ₄ ) ₂ polyhydrate).

  Preparative HPLC was performed on a Gilson instrument equipped with a C18 column, a 215 liquid handler module, and a head pump with a performance of 25 mL / min. The HPLC is operated using Gilson UniPoint system software.

Semi-preparative HPLC conditions for the purification of test compounds:
HPLC system: two Gilson # 305-25 mL pumps, Gilson # 215 liquid handler for injection and collection, and Gilson # 155 UV-Vis absorbance detector (all controlled by Gilson Unipoint V1.91 software) )
Column: Alltech (# 96053) Hyperprep PEP, C-18, 100 Angstrom α, 8 μm, 22 × 250 mm
Flow rate: 15 mL / min Solvent: A: H ₂ O; B: CH ₃ CN
Gradient: 25% -80% B, 40 minutes Detector: Absorbance; λ: 210 & 265 nm.

  The crude material dissolved in acetonitrile at a concentration of about 50-80 mg / 2 mL was injected in each run. Fractions were collected in a volume of 9 mL and the associated absorbance was detected with a UV detector.

  Unless otherwise indicated, all starting materials were obtained from general suppliers such as Aldrich or Sigma.

  The melting point (mp) was measured in a capillary tube on a Buchi 530 melting point instrument and was not corrected.

  Mass spectra were recorded on a Hewlett Packard LC / MSD1100 system using an APCI or electrospray source in either negative mode or positive mode.

Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AMX-II-500 equipped with a reverse probe or QNP probe. For data acquisition, deuterated chloroform (CDCl ₃ ), deuterated acetone (acetone-d ₆ ), deuterated methanol (CD ₃ OD), or deuterated dimethyl using tetramethylsilane as an internal standard. Samples were dissolved in sulfoxide (DMSO-d ₆ ). The chemical shift () is expressed in parts per million (ppm), and the coupling constant (J) is expressed in hertz (Hz), where for the multiplet, the singlet is s, the doublet is d, The doublet is 2d, the doublet doublet is dd, the triplet is t, the quartet is q, the multiplet is m, and the broad singlet is brs.

Detailed Description of the Invention Examples:
Specific Examples for the Preparation of Derivatives of General Formula I The preparation of PL-100, PL-337, and other compounds of this class is provided in US Patent No. 6,632,816 to Stranix et al. .

  The following compounds were prepared from L-lysine derivatives using the procedures summarized in Schemes 1, 1A, 2, 3, 4, and 5 of the present invention.

Example 1
(1S, 5S)-(1- {5-[(4-Amino-benzenesulfonyl) -isobutyl-amino] -6-phosphonooxy-hexylcarbamoyl} -2,2-diphenyl-ethyl) -carbamic acid methyl ester (PL -461) The preparation of the title compound is based on Schemes 1 and 2 of the present invention.

Step A. Preparation of (3S) -3-isobutylamino-azepan-2-one (IV) L-α-amino-caprolactam (22.0 g) was dissolved in cold dichloroethane (DCM, 200 mL). Isobutyraldehyde (12.6 g) was added slowly and stirred until the heat generated was dissipated (water formed on the surface). The cold solution was added to 46.5 g NaBH (OAc) ₃ powder in DCM (0.5 L). AcOH (70 mL) was added to the solution. The slightly cloudy mixture was stirred at 20 ° C. for 4 hours. A 500 mL solution of 2M NaOH was slowly added to the cloudy mixture, the pH was adjusted to 11 with concentrated NaOH solution, and then the mixture was stirred for an additional 20 minutes. After extraction, the DCM layer was dried over MgSO4, filtered and evaporated. The oil thus obtained was allowed to crystallize slowly (27.8 g, 85%) and used in the next step without further purification.

¹ H NMR (CDCl ₃ ): δ 0.93 (d, J = 6.5, 3H), 0.97 (d, J = 6.5, 3H), 1.39 (t, J = 9.8, 1H), 1.47 (m, 1H), 1.78-1.65 (m, 2H), 2.00-1.93 (m, 2H), 2.32-2.2 (m, 2H) 2.38 (t, J = 9.7, 1H), 3.16 (m, 3H), 6.62 (s, 1H (NH)). mp 52-54 ° C. (hexanes).

  For a small sample, the solid was converted to S-methylbenzylurea by adding it to a solution of S-methylbenzylisocyanate in MeCN. In NMR, it was 98% ee.

Step B. Preparation of Nα-isobutyl-Nα- (4-acetamidobenzenesulfonyl) -L-α-amino-α-caprolactam (V) Nα-isobutyl-L-α-amino-caprolactam (IV) (4.1 g free base) Was dissolved in DCM (200 mL) and treated with 4.0 g triethylamine followed by 4-acetamidobenzenesulfonyl chloride (5.2 g). 0.1 g part of dimethylaminopyridine was added and the mixture was stirred for 5 hours. The resulting thick slurry was poured into 500 mL of 0.5M HCl and shaken vigorously. The solid in the biphasic solution was filtered off and washed with cold acetone to give 7.3 g (87%) of a clear product.

¹ H NMR (DMSO-d ₆ ): δ 0.93 (d, J = 6.0, 3H), 0.96 (d, J = 6.0, 3H), 1.39 (t, J = 12. 0, 1H), 1.85-1.65 (m, 3H), 2.08-2.18 (m and s, 6H), 2.90-2.97 (m, 1H), 3.00- 3.06 (m, 2H), 3.35 (dd, J = 14.2, 8.5, 1H), 4.65 (d, J = 8.7, 1H), 6.3 (s, 1H) ), 7.42 (d, J = 8.8, 2H), 7.6 (d, J = 8.8, 2H). mp 230-233 [deg.] C (EtOH).

Step C. (3S) -3-{[4- (acetyl-tert-butoxycarbonyl-amino) -benzenesulfonyl] -isobutyl-amino} -2-oxo-azepan-1-carboxylic acid tert-butyl ester (BOC activity) (VI ) 4.2 g of Nα-isobutyl-Nα- (4-acetamidobenzenesulfonyl) -L-α-amino-caprolactam (V) was suspended in 30 mL of MeCN, sonicated briefly, and any large lumps were crushed . To this white suspension was added 6.7 g (3 eq.) Of di-tert-butyl pyrocarbonate in 10 mL of MeCN. The suspension was stirred with a stir bar and 120 mg of DMAP was added. The solution became clear and pale yellow after a few minutes. TLC (EtOAc) showed one product of Rf 0.9 (starting material Rf 0.4). The solution was poured into 20 mL distilled water, extracted with ether, dried over Na ₂ SO ₄ and evaporated to yield 6.90 g. The sample was recrystallized from hexane.

¹ H NMR (DMSO-d ₆ ): 0.68 (d, J = 6.0, 3H), 0.85 (d, J = 6.0, 3H), 1.39 (s, 10H), 1 .47 (s, 9H), 1.85 to 1.65 (m, 3H), 2.15 (s, 3H), 2.80 (q, J = 4, 1H), 3.10-3.36 (M, 2H), 4.01 (d, J = 8.0, 1H), 4.85 (d, J = 8.7, 1H), 7.32 (d, J = 8.8, 2H) 7.87 (d, J = 8.8, 2H). mp 123-124 ° C.

Step D. Preparation of (1S) -4-amino-N- (5-amino-1-hydroxymethyl-pentyl) -N-isobutyl-benzenesulfonamide (VII-deprotection) (reductive ring opening and deprotection)
3.0 g of (3S) -3-{[4- (acetyl-tert-butoxycarbonyl-amino) -benzenesulfonyl] -isobutyl-amino} -2-oxo-azepan-1-carboxylic acid tert-butyl ester (VI, Step C) is dissolved in ₄₀ mL EtOH followed by 750 mg NaBH ₄ . A clear solution can be obtained by simple heating with a heat gun. TLC shows one streaky spot after 20 minutes (EtOAc). The solution is concentrated to a paste, poured into 40 mL of 1N NaOH, extracted with ethyl acetate, the organic phase is dried over NaSO ₄ and evaporated to give intermediate (VII) product; (1S)-{4-[( 2.8 g of 5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl) -isobutyl-sulfamoyl] -phenyl} -carbamic acid tert-butyl ester (VII) are obtained.

  Dissolve the above intermediate product in 5 mL EtOH and add 5 mL 1 2N HCl. Vigorous gas evolution is observed for several minutes. After 2 hours, the solution is evaporated, basified with concentrated KOH and extracted with EtOAc to yield 1.75 g of a white powder.

¹ H NMR (DMSO-d ₆ ): 0.82 (m, 6H), 0.97-1.12 (m, 2H), 1.15-1.30 (m, 3H), 1.57 (m , 1H), 1.84 (m, 1H), 2.40 (t, J = 7.8, 2H), 2.75 (m, 1H), 2.85 (m, 1H), 3.21 ( m, 1H), 3.44 (d, J = 6.4, 2H), 5.92 (brs, 2H), 6.59 (d, J = 8.0, 2H), 7.39 (d, J = 8.0, 2H).

Step E. Preparation of (2S) -2-methoxycarbonylamino-3,3-diphenyl-propionic acid L-diphenylalanine (241 mg, 1.0 mmol) (Peptech Corp.) in ₅ mL of 1N NaOH and 0.5 mL of saturated Na ₂ CO ₃ Methoxycarbonyloxysuccinimide (carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester) (180 mg, 1.1 mmol) dissolved in 5 mL was added to a solution of pH 10) of the resulting solution. The reaction mixture was then stirred at room temperature for 2 hours. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL of EtOAc and the combined organic phases were washed with 50 mL of 1N HCl. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to an oil that solidified to yield 250 mg (83%) of the desired material. This derivative was used as such in the next step.

Step F. (1S, 5S)-(1- {5-[(4-Amino-benzenesulfonyl) -isobutyl-amino] -6-hydroxy-hexylcarbamoyl} -2,2-diphenyl-ethyl) -carbamic acid methyl ester (PL −100) Using the coupling procedure with HOBt and EDAC described in Example 3 (Step D), the title compound was converted to (1S) -4-amino-N- (5-amino-1-hydroxymethyl). Prepared from -pentyl) -N-isobutyl-benzenesulfonamide (VII-deprotected) (step D) and (2S) -2-methoxycarbonylamino-3,3-diphenyl-propionic acid (step E). The final product was obtained in 67% yield (121 mg).
LC-MS: 625.3 (M + H) ⁺ , purity 95%.

¹ H NMR (CD ₃ OD): δ 0.71-0.85 (m, 2H), 0.88 (d, J = 6.3, 5H), 0.91-0.96 (m, 2H), 1.29-1.34 (m, 1H), 1.41-1.52 (m, 1H) 1.82-1.92 (m, 1H), 2.61-2.68 (m, 1H) 2.81-2.85 (m, 2H), 2.94-3.05 (m, 2H), 3.38-3.40 (t, J = 5.0, 1H), 3.50- 3.51 (m, 1H), 3.52 (s, 3H), 4.28 (d, J = 11.01H), 4.87 (d, J = 11.0, 1H), 6.69 ( d, J = 8.0, 2H), 7.15-718 (m, 2H), 7.20-7.31 (m, 6H), 7.33 (d, J = 7.9, 2H), 7.47 (d, J = 7.5, 1H).
¹³ CNMR (CD ₃ OD): δ 20.0, 20.1, 23.3, 25.4, 28.1, 28.5, 28.9, 38.1, 40.0, 51.2, 51. 6, 53.1, 57.2, 57.4, 59.5, 61.9, 62.4, 112.6, 125.7, 126.2, 126.3, 127.9, 128.1, 128.15, 128.2, 128.4, 128.7, 141.3, 141.9, 152.4, 155.9, 169.9, 172.5.

Step G. (1S, 5S)-{1- [5-[(4-Amino-benzenesulfonyl) -isobutyl-amino] -6- (dimethoxy-phosphoryloxy) -hexylcarbamoyl] -2,2-diphenyl-ethyl} -carbamine Preparation of Acid Methyl Ester PL-100 compound (Product of Step F, 203 mg, 0.325 mmol) was dissolved in dry tetrahydrofuran (3 mL) and 0.2 mL of triethyl phosphate under N ₂ atmosphere. The mixture was stirred at this temperature for 15 minutes, followed by the addition of diethyl chlorophosphate (0.061 mL, 0.423 mmol). Sodium hydride (60% in mineral oil) (17 mg, 0.423 mmol) was added at 0 ° C. The solution was stirred at 0 ° C. for 1 hour and at room temperature for 12 hours. 20 mL of Amberlite XAD-2 was added to the solution and the beads were mixed well with the solvent. To the mixture was added 2 mL of ice water and the THF was removed by evaporation. The beads were then washed 6 times with 100 mL of distilled water and then extracted 3 times with ethyl acetate (30 mL). The combined phases were evaporated and the residue was dried under high vacuum. The crude product was purified by flash chromatography using ethyl acetate / hexane (8/2) and then 100% EtOAc as eluent. The yield of this reaction is 152 mg, 61%.
LC-MS: 761.2 (M + H) ⁺ , purity 90%

¹ H NMR (CD ₃ OD): δ 0.68-0.75 (m, 1H), 0.75-0.84 (m, 1H), 0.84-1.10 (m, 9H), 21-1.50 (m, 8H), 1.88 (m, 1H), 2.58-2.71 (m, 1H), 2.80-2.89 (m, 1H), 2.89- 3.08 (m, 2H), 3.49-3.60 (s, 3H), 3.65-3.74 (m, 1H), 3.85-3.95 (m, 1H), 3. 97-4.02 (m, 1H), 4.07-4.21 (m, 4H), 4.29 (d, J = 10.8, 1H), 6.71 (d, J = 8.0) , 2H), 7.10-7.20 (m, 2H), 7.20-7.32 (m, 5H), 7.32-7.45 (m, 3H), 7.50 (d, J = 7.5, 2H), 7.86 (brs, 1H).
³¹ P NMR (CD ₃ OD): δ 1.62.

Step H. (1S, 5S)-(1- {5-[(4-Amino-benzenesulfonyl) -isobutyl-amino] -6-phosphonooxy-hexylcarbamoyl} -2,2-diphenyl-ethyl) -carbamic acid methyl ester (PL -461) Preparation The product of step G prepared above (152 mg) was dissolved in anhydrous dichloromethane (3.0 mL). Trimethylsilyl bromide (0.5 mL) was added at 0 ° C. The mixture was stirred at this temperature for 1 hour and stirred overnight at room temperature. The solvent was evaporated and 0.2 mL water was added to the residue. 3 mL EtOH was added, mixed and evaporated. This process was repeated three times and the residue was dried in vacuo. The yield of the title derivative of this first example was 98 mg, 70%.
LC-MS: 705.2 (M + H) ^<+> , purity 95%.

¹ H NMR (CD ₃ OD): δ 0.65-0.73 (m, 1H), 0.75-0.83 (m, 1H), 0.89 (d, J = 5.6, 8H), 1.27-1.38, (m, 1H), 1.42-4.55 (m, 1H), 1.82-1.94 (m, 1H), 2.57-2.68 (m, 1H), 2.78-2.90 (m, 1H), 2.91-3.09 (m, 2H), 3.54 (s, 3H), 3.60-3.72 (m, 1H) 3.87-4.05 (m, 1H), 4.00 (m, 1H), 4.29 (d, J = 11.3, 1H), 4.90 (d, J = 11.4, 1H), 6.73 (d, J = 8.0, 2H), 7.13-7.22 (m, 2H), 7.22-7.33 (m, 6H), 7.33-7. 45 (m, 2H), 7.51 (d, J = 7.5, 2H).
³¹ P NMR (CD ₃ OD): δ 2.80.

Example 2: (1S, 5S)-(1- {5-[(4-Amino-benzenesulfonyl) -isobutyl-amino] -6-phosphonooxy-hexylcarbamoyl} -2,2-diphenyl-ethyl) -carbamic acid Preparation of methyl ester sodium salt (PL-462) 70.7 mg of the final product of Example 1 is added to 1 mL of 0.1 N NaOH and diluted with 1 mL of distilled water. The solution is then frozen and lyophilized. The yield of the desired material is 67.2 mg (92%), purity 95%.

¹ H NMR (CD ₃ OD): δ 0.72-0.83 (m, 1H), 0.90 (d, J = 5.8, 9H), 1.26-1.38 (m, 1H), 1.53-1.65 (m, 1H), 1.88-2.00 (m, 1H), 2.60-2.70 (m, 1H), 2.79-2.89 (m, 1H) ), 2.98-3.00 (m, 1H), 3.00-3.08 (m, 1H), 3.54 (s, 3H), 3.58-3.71 (m, 1H), 3.72-3.83 (m, 1H), 3.84-3.95 (m, 1H), 4.28 (d, J = 11.1, 1H), 4.91 (d, J = 11) 0.0, 1H), 6.70 (d, J = 7.6, 2H), 7.12-7.22 (m, 2H), 7.22-7.32 (m, 6H), 7.33 −7.40 (m, 2H), 7.50 (d, J = 7.7, H).
³¹ P NMR (CD ₃ OD): δ 3.13.

Example 3: (1S, 5S)-(1- {5-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6-phosphonooxy-hexylcarbamoyl} -2-naphthalen-2-yl-ethyl)- Preparation of Carbamate Methyl Ester (PL-507) The preparation of the title compound is based on Scheme 2 of the present invention.

Step A. Preparation of (1S)-(4-{[5-tert-butoxycarbonylamino-1- (dimethoxyphosphoryloxymethyl) -pentyl] -isobutyl-sulfamoyl} -phenyl) -carbamic acid tert-butyl ester (VIII) )-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl) -isobutyl-sulfamoyl] -phenyl} -carbamic acid tert-butyl ester (VII) (Example 1, Step D) 2. 00 g (3.7 mmol) is dissolved in 0.63 mL of triethyl phosphate and 10 mL of THF at 0 ° C. under an inert argon atmosphere. 0.63 mL (4.44 mmol) of diethyl chlorophosphate is added, followed by 0.25 g (6.2 mmol) of 60% NaH in oil in several portions. The mixture is warmed to room temperature and left stirring for 2 hours (LC-MS showed completion after 1 hour). To this solution, 20 mL of Amberlite XAD-2 resin is added, the slurry is mixed well and added to 200 mL of ice water. After stirring for 15 minutes, the resin suspension is filtered and the resin is washed several times with distilled water (500 mL). The desired product is desorbed from the resin with acetone (5 × 50 mL), EtOAc (5 × 50 mL), then the organic phase is dried over Na ₂ SO ₄ . After evaporating 2.66 g (89%) of the solvent, a clear oil is obtained. The crude product contains a fraction with two diethyl phosphates, which is used directly in the next step.

¹ H NMR (CD ₃ OD): δ 0.91 (d, J = 6.3, 6H), 1.11-1.21 (m, 2H), 1.33 (t, J = 6.9, 10H) ), 1.43 (s, 9H), 1.53 (s, 10H), 1.90-1.97 (m, 1H), 2.88-2.96 (m, 3H), 2.96- 3.04 (m, 1H), 3.81-3.90 (m, 1H), 3.91-3.99 (m, 1H), 4.01-4.14 (m, 4H), 7. 61 (d, J = 8.3, 2H), 7.72 (d, J = 8.4, 2H).
³¹ P NMR (CD ₃ OD): δ 1.59.

Step B. Preparation of (2S) -phosphate 6-amino-2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -hexyl ester diethyl ester (IX) The crude product obtained in the previous step (VIII, 2.66 g) is dissolved in 12 mL EtOH. Add 4 mL of concentrated HCl, briefly heat to 70 ° C., then leave at room temperature for 3 hours. The solvent is evacuated and the residue is triturated with 50 mL of ether. The thick residue is then dissolved in 3 mL of ice water and the pH is adjusted to 12 with 50% NaOH. The resulting thick slurry is extracted with EtOAc (3 × 50 mL) and the organic phase is dried over Na ₂ SO ₄ . After filtration of the desiccant, the organic phase is evacuated to yield 1.84 g (98%) of the desired product (IX).
LC-MS: 480.2 (M + H) ^<+> , purity 95%.

¹ H NMR (CD ₃ OD): δ 0.91 (s, 6H), 1.11-1.26 (m, 3H), 1.28-1.43 (m, 8H), 1.45-1. 51 (m, 1H), 1.52-1.61 (m, 1H), 1.89-1.96 (m, 1H), 2.56 (t, J = 6.7, 2H); 85-2.91 (m, 1H), 2.98-3.11 (m, 1H), 3.79-3.99 (m, 1H), 3.94 (d, J = 5.3, 1H) ) 4.09-4.11 (m, 4H), 6.69 (d, J = 7.9, 2H), 7.50 (d, J = 7.9, 2H).
³¹ P NMR (CD ₃ OD): δ 1.61.

Step C. Preparation of (2S) -2-methoxycarbonylamino-3-naphthalen-2-yl-propionic acid (or L-Moc-2-naphthylalanine) L-2-in in ₅ mL of 1N NaOH and 0.5 mL of saturated Na ₂ CO ₃ Methoxycarbonyloxysuccinimide (187 mg, 1.1 mmol) dissolved in 5 mL was added to a solution of naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) (pH 10 of the resulting solution). The reaction mixture was then stirred at room temperature for 2 hours. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL of EtOAc and the combined organic phases were washed with 50 mL of 1N HCl. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to an oil that solidified to yield 200 mg (73%) of the desired material. This intermediate (referred to as the N-substituted amino acid) was used in the next step without further purification.

Step D. (1S, 5S)-(1- {5-[(4-Amino-benzenesulfonyl) -isobutyl-amino] -6-phosphonooxy-hexylcarbamoyl} -2-naphthalen-2-yl-ethyl) -carbamic acid methyl ester Preparation of (PL-507) 100 mg of L-Moc-2-naphthylalanine (Step C) was activated with 100 mg EDAC and 57 mg HOBt in 1.5 mL DMF for 30 minutes. Then 100 mg of phosphoric acid 6-amino-2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -hexyl ester diethyl ester (Step B) is added and left stirring at room temperature for 1 hour. 40 mL of 1M K ₂ CO ₃ was added to the DMF solution and left for 10 minutes. Then 50 mL of EtOAc was added and the mixture was then stirred vigorously. Separation of the EtOAc phase was performed, followed by extraction once with 5% citric acid (50 mL), then three times with water (50 mL) and finally with brine. The organic phase was separated and evaporated. The residue was dissolved in 50 mL DCM and evaporated again. The residue is redissolved in 50 mL DCM and 0.5 mL TMSBr is added. The solution was left overnight (16 hours). DCM was evacuated and ice-cold MeOH: water 1: 1 solution was added, stirred briefly and evacuated. The residue is triturated with ether and then dissolved in 1N NaOH. The clear solution was extracted with ether and the aqueous phase was acidified with 6N HCl. The white precipitate was then collected by filtration and dried in vacuo overnight. 88 mg of the title compound were obtained.
LC-MS: 679.8 (M + H) ^<+> , purity 95%.

¹ H NMR (CD ₃ OD): δ 0.89-0.98 (m, 8H), 1.15 (m, 2H), 1.35 (m, 1H), 1.45 (m, 1H), 1 .88 (m, 1H), 2.84 (m, 2H), 2.98 (m, 1H), 3.01 (m, 2H), 3.24 (m, 1H), 3.56 (s, 3H), 3.60 (m, 1H), 3.81 (m, 1H), 3.99 (m, 1H), 4.39 (t, J = 6.8, 1H), 6.91 (d , J = 8.0, 2H), 7.34 (d, J = 8.0, 1H), 7.45 (m, 2H), 7.58 (d, J = 8.0, 2H), 7 .66 (s, 1H), 7.70-7.82 (m, 3H).
³¹ P NMR (CD ₃ OD): δ 2.56.

Example 4: (2S, 2S) phosphoric acid mono- (2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- {2-[(morpholine-4-carbonyl) -amino] -3- Preparation of naphthalen-1-yl-propionylamino} -hexyl) ester (PL-498)

Step A. Preparation of (2S) -2-[(morpholin-4-carbonyl) -amino] -3-naphthalen-1-yl-propionic acid L-1-naphthylalanine ( ₅ mL of 1N NaOH and 0.5 mL of saturated Na ₂ CO ₃ ( To a solution of 215 mg, 1 mmol) (Peptech Corp.) (H10 of the resulting solution), morpholine-4-carbonyl chloride (150 mg, 1.0 mmol) dissolved in 5 mL was added. The reaction mixture was then stirred at room temperature for 2 hours. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL EtOAc and the combined organic phases were washed with 50 mL 1N HCl. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to an oil that solidified to yield 125 mg (38%) of the desired material. This compound was used as such in the next step.

Step B. (2S, 2S) Phosphoric acid mono- (2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- {2-[(morpholine-4-carbonyl) -amino] -3-naphthalene-1- Preparation of yl-propionylamino} -hexyl) ester (PL-498) This compound was converted to (2S) -2-[(morpholin-4-carbonyl) -amino] -3-naphthalen-1-yl-propionic acid (present Prepared as in the preparation of the product of Example 3 (Step D) using 100 mg of Example Step A). The resulting precipitated residue was further purified by reverse phase preparative HPLC. 41 mg of final compound was obtained.
LC-MS: 734.8 (M + H) ⁺ , purity 95%.

¹ H NMR (CD ₃ OD): δ 0.83-0.98 (m, 8H), 1.00-1.25 (m, 4H), 1.45-1.52 (m, 1H), 52-1.66 (m, 1H), 1.88-1.99 (m, 1H), 2.77-2.92 (m, 2H), 2.98-3.16 (m, 3H), 3.40-3.49 (m, 1H), 3.50-3.56 (m, 6H), 3.67-3.69 (m, 1H), 3.81-3.89 (m, 1H) ), 3.99-4.05 (m, 1H), 4.59 (t, J = 6.0, 1H), 6.75 (d, J = 8.0, 2H), 7.30-7 .60 (m, 7H), 7.75 (d, J = 8.0, 1H), 7.90 (d, J = 7.8, 1H), 8.23 (d, J = 7.82H) .
³¹ P NMR (CD ₃ OD): δ 2.71.

Example 5: (2S, 2S) -phosphate mono- {6- (2-acetylamino-3,3-diphenyl-propionylamino) -2-[(4-amino-benzenesulfonyl) -isobutyl-amino]- Preparation of hexyl} ester (PL-504)

Step A. Preparation of (2S) -2-acetylamino-3,3-diphenyl-propionic acid A solution of L-diphenylalanine (100 mg, 0.4 mmol) (Peptech Corp.) in ₅ mL of 1N NaOH and 0.5 mL of saturated Na ₂ CO _3. To (pH 10 of the obtained solution), acetyl chloride (0.5 mmol) dissolved in 5 mL was added. The reaction mixture was then stirred at room temperature for 2 hours. The alkaline solution was extracted once with ether (10 mL) and the aqueous phase was acidified with 1N HCl. This was extracted twice with 20 mL of EtOAc and the combined organic phases were washed with 50 mL of 1N HCl. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to an oil that solidified to yield 70 mg (60%) of the desired material. This crude intermediate was used as such in the next step.

Step B. (2S, 2S) -phosphate mono- {6- (2-acetylamino-3,3-diphenyl-propionylamino) -2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -hexyl} ester ( PL-504) Preparation of the product of Example 3 (Step D) using 100 mg of (2S) -2-acetylamino-3,3-diphenyl-propionic acid (this Example Step A). Produced as prepared. The final product was obtained in 30% yield (30 mg).
LC-MS: 689.3 (M + H) ⁺ , purity 95%.

¹ H NMR (CD ₃ OD): δ 0.77-1.04 (m, 9H), 1.10-1.17 (m, 1H), 1.23-1.49 (m, 1H), 46-1.57 (m, 1H), 1.78 (s, 3H), 1.88-1.99 (m, 1H), 2.80-2.92 (m, 2H), 2.92- 3.08 (m, 2H), 3.63-3.75 (m, 1H), 3.79-3.95 (m, 1H), 4.00 (m, 1H), 4.34 (d, J = 11.3, 1H), 5.19-5.28 (m, 1H), 6.77-6.85 (m, 2H), 7.10-7.20 (m, 2H), 7. 27-7.33 (m, 6H), 7.32-7.41 (m, 2H), 7.49-7.62 (m, 2H).
³¹ P NMR (CD ₃ OD): δ 2.70.

Example 6: (1S, 5S)-(1- {5-[(4-Amino-3-fluoro-benzenesulfonyl) -isobutyl-amino] -6-phosphonooxy-hexylcarbamoyl} -2,2-diphenyl-ethyl Preparation of) -carbamic acid methyl ester (PL-515) First methodology: The preparation of the title compound is based on Scheme 3 of the present invention.

Step A. (1- {5-[(4-Amino-3-fluoro-benzenesulfonyl) -isobutyl-amino] -6-hydroxy-hexylcarbamoyl} -2,2-diphenyl-ethyl) -carbamic acid methyl ester (X) ( Preparation of PL-337) The product of Example 1, Step F (0.624 g, 1 mmol) is dissolved in 5 mL of MeCN at 24 ° C. SelectFluor 0.35 g (1 mmol) is added in one portion and stirred for 1 hour. 1 mL of water was added and the solution was directly injected into preparative reverse phase HPLC. The product was collected and lyophilized to give a white solid in a yield of 250 mg (38%).
LC-MS: 643.3 (M + H) ⁺ , purity 99%.

¹ H NMR (MeOD): δ 0.71-0.85 (m2H), 0.88 (d, J = 6.3, 6H), 0.91-0.96 (m, 2H), 1.21- 1.29 (m, 1H), 1.41-1.52 (m, 1H) 1.82-1.92 (m, 1H), 2.61-2.68 (m, 1H), 2.81 -2.85 (m, 2H), 2.94-3.05 (m, 2H), 3.38-3.40 (t, J = 5, 1H), 3.49-3.52 (m, 5H), 4.28 (d, J = 10, 1H), 4.87 (d, J = 10, 1H), 6.90 (t, J = 8.3, 1H), 7.20 (m, 2H) ), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H).

Step B. (1S, 5S)-{1- [5-[(4-Amino-3-fluoro-benzenesulfonyl) -isobutyl-amino] -6- (dimethoxy-phosphoryloxy) -hexylcarbamoyl] -2,2-diphenyl- Preparation of ethyl} -carbamic acid methyl ester The product of Step A was phosphorylated with chlorodiethyl phosphate, followed by the procedure described in Example 1, Step G. Yield 157 mg, 68%.
LC-MS: 779.3 (M + H) ⁺ , purity 95%.

¹ H NMR (CD ₃ OD): δ 0.82 (m, 1H), 0.92 (d, J = 6.2, 8H), 0.96 (m, 3H), 1.36 (d, J = 3.7, 6H), 1.90 (m, 1H), 2.69 (m, 1H), 2.89 (m, 1H), 2.98 (m, 2H), 3.56 (s, 3H) 3.74 (m, 1H), 3.93 (m, 1H), 4.03 (m, 1H), 4.12 (q, J = 7.5 and 14.8, 4H), 4. 32 (d, J = 11.4, 1H), 4.92 (d, J = 11.4, 1H), 6.90 (t, J = 8.3, 1H), 7.20 (m, 2H) ), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H).
³¹ P NMR (CD ₃ OD): δ 1.65.

Step C. (1S, 5S)-(1- {5-[(4-Amino-3-fluoro-benzenesulfonyl) -isobutyl-amino] -6-phosphonooxy-hexylcarbamoyl} -2,2-diphenyl-ethyl) -carbamic acid Preparation of methyl ester (XI) (PL-515) Deprotection was performed using the procedure described in Example 1, Step G. Yield 101 mg.
LC-MS: 723.2 (M + H) ^<+> , purity 95%.

¹ H NMR (CD ₃ OD): δ 0.65-0.77 (m, 1H), 0.77-0.85 (m, 1H), 0.85-1.05 (m, 9H), 25-1.39 (m, 1H), 1.40-1.52 (m, 1H), 1.82-1.98 (m, 1H), 2.58-2.72 (m, 1H), 2.82-2.92 (m, 1H), 2.92-3.05 (m, 2H), 3.54 (s, 3H), 3.64-3.75 (m, 1H), 80-3.92 (m, 1H), 3.91-4.04 (m, 1H), 4.29 (d, J = 11.4, 1H), 7.19 (t, J = 6.6) , 1H), 7.13-7.21 (m, 2H), 7.22-7.33 (m, 6H), 7.34-7.38 (m, 2H), 7.39-7.48. (M, 2H).
³¹ P NMR (CD ₃ OD): δ 2.74.

  Second methodology: The preparation of the title compound is based on Scheme 4 of the present invention.

Step A. (1S, 5S)-(1- {5-[(4-Amino-benzenesulfonyl) -isobutyl-amino] -6-phosphonooxy-hexylcarbamoyl} -2,2-diphenyl-ethyl) -carbamic acid methyl ester (PL Preparation of -461) (2S) -2-Methoxycarbonylamino-3,3-diphenyl-propionic acid ((Example 1, Step E) 0.9 g, 3 mmol) in EMF (1.7 g) in DMF (5 mL). , 9 mmol) and HOBt (1.2 g, 9 mmol). To this solution is added 1.17 g of (2S) -phosphate 6-amino-2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -hexyl ester diethyl ester (IX) (Example 3, Step B) And the mixture was stirred for 3 hours. Amberlite XAD-2 resin 20 g was then added and the beads were left soaked for 10 minutes. The resin was transferred to a glass filter and washed thoroughly with distilled water (400 mL) and 1M NaHCO ₃ 200 mL. The beads were then washed with 4 × 50 ml MeOH followed by 200 mL EtOAc. The organic phase was evaporated. The residue was adsorbed onto silica gel, passed through a short silica gel column (EtOAc) and, after evaporation, 2.4 g (83%) of a white solid was formed.

¹ NMR was the same as in Example 1, Step H.

Step B. (1S, 5S)-{1- [5-[(4-Amino-3-fluoro-benzenesulfonyl) -isobutyl-amino] -6- (dimethoxy-phosphoryloxy) -hexylcarbamoyl] -2,2-diphenyl- Preparation of ethyl} -carbamic acid methyl ester (XII) The product of step A above, (1S, 5S)-(1- {5-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6-phosphono Oxyhexylcarbamoyl} -2,2-diphenyl-ethyl) -carbamic acid methyl ester (0.555 g, 0.73 mmol) was dissolved in 5 mL MeCN. Selectfluor (0.26 g, 0.7 mmol) was added and the mixture was stirred for 30 minutes. The mixture was purified by reverse phase preparative HPLC and lyophilized to produce 278 mg (48% yield) of a white solid.

¹ H NMR was the same as the previous one. See the first methodology above.

Step C. (1S, 5S)-(1- {5-[(4-Amino-3-fluoro-benzenesulfonyl) -isobutyl-amino] -6-phosphonooxy-hexylcarbamoyl} -2,2-diphenyl-ethyl) -carbamic acid Preparation of the methyl ester (XIII in this particular case is compound XI) (PL-515) The procedure for producing this derivative was as described in the deprotection step of the methodology above. The yield after reverse phase HPLC was 139 mg, 70%.

¹ H NMR was the same as the previous one. See the first methodology above.

Example 7: (2S, 2S) -acetic acid 2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- (2-methoxycarbonylamino-3,3-diphenyl-propionylamino) -hexyl ester ( Preparation of PL-521) The preparation of the title derivative is based on Scheme 5 of the present invention.

Step A. Preparation of (2S) -acetic acid 6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl) -isobutylamino] -hexyl ester (XIV, R _1A = CH ₃ ) anhydrous CH ₂ Cl (1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl) -isobutyl-sulfamoyl] -phenyl} -carbamic acid tert-butyl ester in ₂ (3 mL) (Example 1, To a stirred solution of the intermediate product of step D (VII), 97 mg, 0.18 mmol) was added N, N-dimethylaminopyridine (22 mg, 0.18 mmol) and acetic anhydride (0.014 mL, 0.18 mmol). did. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated. Ethyl acetate (50 mL) was added and the organic layer was washed with water (30 mL), then dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate. The yield obtained was quantitative (100 mg).
LC-MS: 586.2 (M + H) ⁺ , purity 95%.

Step B. Preparation of (2S) -acetic acid 6-amino-2-[(4-amino-benzenesulfonyl) -isobutylamino] -hexyl ester (XV, R _1A = CH ₃ ) This derivative is described in Example 15, Step B As prepared from (2S) -acetic acid 6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl) -isobutylamino] -hexyl ester. The yellow solid (66 mg) was used in the next reaction without purification.
LC-MS: 386.2 (M + H) ^<+> , purity 95%.

Step C. (2S, 2S) -acetic acid 2-[(4-amino-benzenesulfonyl) -isobutylamino] -6- (2-methoxycarbonylamino-3,3-diphenyl-propionylamino) -hexyl ester (XVI, R _1A = CH ₃₎ (the PL-521) this derivative prepared and as described in example 15, step B, (2S) - acetic acid 6-amino-2 - [(4-amino-benzenesulfonyl) - - isobutyl - amino ] -Hexyl ester (product of Step B). The final product was purified by flash chromatography using an eluent mixture of hexane / ethyl acetate (2/8). A yellow solid was obtained in 70% yield (70 mg).
LC-MS: 667.3 (M + H) ⁺ , purity 95%.

¹ H NMR (acetone-d ₆ ): δ 0.85-0.97 (m, 12H), 1.21-1.41 (m, 2H), 1.88-2.00 (s, 3H), 2 .59-2.69 (m, 1H), 2.83-2.90 (m, 1H), 2.90-3.01 (m, 1H), 3.01-3.10 (brs, 1H) 3.45-3.60 (s, 3H), 3.70-3.80 (m, 1H), 3.93-4.00 (m, 1H), 4.00-4.11 (m, 1H), 4.38-4.45 (d, J = 11.0, 1H), 4.89-4.98 (t, J = 10.0, 1H), 5.43-5.58 (brs) , 1H), 6.28-6.48 (d, J = 8.9, 1H), 6.72-6.83 (d, J = 8.0, 2H), 6.85-6.93 ( brs, 1H), 7.12-7.22 (t J = 7.4, 1H), 7.21-7.31 (d, J = 7.0, 4H), 7.31-7.45 (m, 5H), 7.48-7.57 (d , J = 8.0, 2H).

Example 8: (2S, 2S) -nicotinic acid 2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- (2-methoxycarbonylamino-3,3-diphenyl-propionylamino) -hexyl ester Preparation of (PL-520)

Step A. Preparation of (2S) -nicotinic acid 6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl) -isobutyl-amino] -hexyl ester (XIV, R _1A = 3-pyridyl) 1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl) -isobutyl-sulfamoyl] -phenyl} -carbamic acid tert-butyl ester (intermediate product of Example 1 (VII)) Step D, 130 mg, 0.24 mmol) in anhydrous DMF (1 mL), 0.066 mL (0.48 mmol) of triethylamine, followed by EDC (120 mg, 0.65 mmol), HOBt (88 mg, 0.65 mmol), And treated with nicotinic acid (27 mg, 0.22 mmol) I managed. The mixture was stirred overnight at room temperature. The product was extracted with ethyl acetate (40 mL) and water (40 mL). The organic phase was separated, dried over Na ₂ SO ₄ and then evaporated to give 200 mg of crude product. This compound was purified by flash chromatography using ethyl acetate as eluent. A clear oil was obtained with a yield of 100% (150 mg).
LC-MS: 649.3 (M + H) ⁺ , 95% purity.

¹ H NMR (acetone-d ₆ ): δ 0.90-1.14 (d, J = 5.9, 6H), 1.31-1.42 (m, 2H), 1.48 (s, 9H) 1.51-1.55 (m, 2H), 1.59 (s, 9H), 1.62-1.69 (m, 1H), 1.72-1.83 (m, 1H), 3 .00-3.11 (m, 2H), 3.11-3.17 (m, 1H), 3.19-3.27 (m, 1H), 4.15-4.24 (m, 1H) 4.35-4.44 (t, J = 9.1, 1H), 4.50-4.58 (dd, J = 4.4 and 11.5, 1H), 5.89-5.99. (Brs, 1H), 7.53-7.60 (m, 1H), 7.70-7.77 (d, J = 8.2, 2H), 7.80-7.87 (d, J = 8.2, 2H), 8.24-8.31 (d, J = 7 3,1H), 8.75-8.82 (m, 1H), 8.82-8.88 (m, 1H), 9.12-9.18 (brs, 1H).

Step B. Preparation of (2S) -nicotinic acid 6-amino-2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -hexyl ester (XV, R _1A = 3-pyridyl) product of step A, (2S) - nicotinic acid 6-tert-butoxycarbonylamino -2 - [(4-tert- butoxycarbonylamino-benzenesulfonyl) - - isobutyl - amino] - hexyl ester (150 mg, 0.23 mmol) in _CH 2 _Cl in 2 (5 mL) Dissolve and add trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was extracted with ethyl acetate (40 mL) and NaOH 1M (40 mL) (pH = 10). The organic portion was separated, dried over Na ₂ SO ₄ and evaporated. The residue (100 mg) was used in the next reaction without further purification. The yield was quantitative.
LC-MS: 449.2 (M + H) ⁺ , purity 95%.

Step C. (2S, 2S) -nicotinic acid 2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- (2-methoxycarbonylamino-3,3-diphenyl-propionylamino) -hexyl ester (PL-520 The product of Step B, (2S) -nicotinic acid 6-amino-2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -hexyl ester (100 mg, 0.22 mmol) was added to anhydrous DMF (2 mL). ), 0.062 mL (0.45 mmol) of triethylamine, followed by EDC (100 mg, 0.56 mmol), HOBt (75 mg, 0.56 mmol), and (2S) -2-methoxycarbonylamino-3,3- Treated with diphenyl-propionic acid (56 mg, 0.19 mmol). The mixture was stirred overnight at room temperature. The product was extracted with ethyl acetate (40 mL) and water (40 mL). The organic layer was separated, dried over Na ₂ SO ₄ and then evaporated to give 160 mg of crude oil. The residue was purified by flash chromatography using an eluent mixture of hexane / ethyl acetate (2/8). The title compound was obtained as a clear oil in 20% yield (25 mg).
LC-MS: 730.2 (M + H) ^<+> , purity 95%.

¹ H NMR (acetone-d ₆ ): δ 0.80-0.97 (m, 9H), 0.97-1.13 (m, 2H), 1.26-1.40 (m, 1H), 1 .40-1.57 (m, 1H), 2.61-2.73 (m, 1H), 2.86-2.98 (m, 2H), 3.00-3.17 (m, 2H) 3.45-3.59 (s, 3H), 3.91-4.00 (m, 1H), 4.24-4.34 (m, 1H), 4.34-4.47 (m, 2H), 4.90-4.99 (t, J = 9.7, 1H), 6.35-6.44 (m, 1H), 6.68-6.79 (d, J = 7.9). , 1H), 6.91-7.00 (brs, 1H), 7.13-7.22 (m, 2H), 7.22-7.31 (m, 3H), 7.35-7.48. (M, 4H), 7.49-7.64 (m, 2H) , 7.75-7.84 (m, 1H), 8.25-8.36 (m, 1H), 8.76-8.88 (brs, 1H), 9.12-9.26 (brs, 1H).

Example 9: (2S, 2S) -Dimethylamino-acetic acid 2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- (2-methoxycarbonylamino-3,3-diphenyl-propionylamino)- Preparation of hexyl ester (PL-534)

Step A. (2S) -Dimethylamino-acetic acid 6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl) -isobutyl-amino] -hexyl ester (XIV, R _1A = (CH ₃ ) ₂ NCH ₂ - a) preparation of the title compound, example 15, as described in step a, using N, the N- dimethylglycine, (1S) - {4 - [(5-tert- butoxycarbonylamino - 1-hydroxymethyl-pentyl) -isobutyl-sulfamoyl] -phenyl} -carbamic acid tert-butyl ester (Example 1, intermediate product (VII) of Step D). A clear oil was obtained with a yield of 100% (150 mg).
LC-MS: 629.3 (M + H) ⁺ , purity 95%.

¹ H NMR (acetone-d ₆ ): δ 0.81-0.95 (d, J = 6.1, 6H), 1.18-1.30 (m, 2H), 1.32-1.43 ( s, 9H), 1.43-1.52 (s, 8H), 1.52-1.62 (m, 1H), 1.93-2.00 (m, 1H), 2.19-2. 29 (s, 4H), 2.69-2.80 (m, 4H), 2.90-3.05 (m, 6H), 3.60-3.65 (m, 1H), 3.85- 3.97 (m, 1H), 3.98-4.08 (m, 1H), 4.08-4.14 (m, 1H), 5.78-5.88 (m, 1H), 7. 68-7.80 (m, 3H), 8.80-8.88 (brs, 1H).

Step B. Preparation of (2S) -dimethylamino-acetic acid 6-amino-2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -hexyl ester (XV, R _1A = (CH ₃ ) ₂ NCH ₂ —) The derivative was prepared as described in Example 15, Step B, (2S) -dimethylamino-acetic acid 6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl) -isobutyl-amino. Prepared from] -hexyl ester. The final product (100 mg) was used as such in the next step.
LC-MS: 429.3 (M + H) ⁺ , purity 90%.

Step C. (2S, 2S) -Dimethylamino-acetic acid 2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- (2-methoxycarbonylamino-3,3-diphenyl-propionylamino) -hexyl ester (PL -534) This title compound was prepared from (2S) -dimethylamino-acetic acid 6-amino-2-[(4-amino-benzenesulfonyl) -isobutyl-amino] as described in Example 15, Step C. -Prepared from hexyl ester. The crude product was purified by LC-prep. The final compound was obtained in 10% yield (10 mg).
LC-MS: 710.3 (M + H) ^<+> , 92% purity.

¹ H NMR (acetone-d ₆ ): δ 0.81-0.98 (m, 12H), 1.14-1.30 (m, 2H), 1.31-1.45 (m, 1H), 2 58-2.77 (m, 2H), 2.79-2.90 (m, 2H), 3.42-3.56 (s, 3H), 3.75-3.85 (m, 1H) 3.9-4.17 (m, 3H), 4.23-4.35 (m, 1H), 4.36-4.45 (m, 1H), 4.86-4.96 (m, 1H), 6.33-6.42 (m, 1H), 6.74-6.83 (m, 1H), 6.85-6.90 (m, 1H), 7.12-7.22 ( m, 3H), 7.23-7.31 (m, 4H), 7.31-7.44 (m, 5H), 7.47-7.55 (m, 1H), 7.73-7. 80 (m, 1H).

Example 10: (2S, 2S) -2-Amino-3-methyl-butyric acid 2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- (2-methoxycarbonylamino-3,3-diphenyl -Propionylamino) -hexyl ester (PL-530)

Step A. (2S) -2-Benzyloxycarbonylamino-3-methyl-butyric acid 6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl) -isobutyl-amino] -hexyl ester (XIV, Preparation of R _1A = (CH ₃ ) ₂ CHCH (NH ₂ )-) This title compound was described in Example 15, Step A using (2S) -2-benzyloxycarbonylamino-3-methyl-butyric acid. (1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl) -isobutyl-sulfamoyl] -phenyl} -carbamic acid tert-butyl ester (Example 1, Step D) Intermediate product (VII)). The crude product was purified by flash chromatography eluting with a mixture of hexane / ethyl acetate (1/1). The yield obtained was 100% (150 mg).
LC-MS: 777.3 (M + H) ⁺ , purity 95%.

¹ H NMR (acetone-d ₆ ): δ 0.80-1.00 (m, 14), 1.13-1.28 (s, 2H), 1.30-1.44 (s, 11H), 1 .45-1.56 (s, 10), 1.58-1.67 (m, 1H), 2.87-3.04 (m, 4H), 3.84-3.97 (m, 1H) 3.97-4.12 (m, 2H), 4.12-4.21 (m, 1H), 4.99-5.14 (m, 2H), 5.78-5.89 (m, 1H), 6.38-6.52 (m, 1H), 7.24-7.34 (m, 1H), 7.34-7.41 (m, 2H), 7.65-7.83 ( m, 4H), 8.77-8.86 (m, 1H).

Step B. (2S) -Benzyloxycarbonylamino-3-methyl-butyric acid 6-amino-2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -hexyl ester (XV, R _1A = (CH ₃ ) ₂ CHCH ( NH ₂₎ -) preparation of

This derivative was prepared as described in Example 15, Step B, (2S) -2-benzyloxycarbonylamino-3-methyl-butyric acid 6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonyl Prepared from amino-benzenesulfonyl) -isobutyl-amino] -hexyl ester (product of Step A). The final compound was obtained in quantitative yield (110 mg) and used in the next step without purification.
LC-MS: 577.3 (M + H) ⁺ , purity 90%.

Step C. (2S, 2S) -2-Benzyloxycarbonylamino-3-methyl-butyric acid 2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- (2-methoxycarbonylamino-3,3-diphenyl- Preparation of propionylamino) -hexyl ester The title compound was prepared as described in Example 15, Step C, with (2S) -benzyloxycarbonylamino-3-methyl-butyric acid 6-amino-2-[(4-amino- Obtained from (benzenesulfonyl) -isobutyl-amino] -hexyl ester (product of Step B). A clear oil was obtained in 86% yield (120 mg).
LC-MS: 858.3 (M + H) ^<+> , purity 95%.

Step D. (2S, 2S) -2-Amino-3-methyl-butyric acid 2-[(4-amino-benzenesulfonyl) -isobutyl-amino] -6- (2-methoxycarbonylamino-3,3-diphenyl-propionylamino) Preparation of hexyl ester (PL-530) (2S, 2S) -2-benzyloxycarbonylamino-3-methyl-butyric acid 2-[(4-amino-benzenesulfonyl) -isobutyl-amino in anhydrous THF (8 mL) ] -6- (2-methoxycarbonylamino-3,3-diphenyl-propionylamino) -hexyl ester (Step C, 120 mg, 0.14 mmol) in a stirred solution of palladium activated carbon 10% wt (160 mg) under nitrogen atmosphere Was added. The mixture was reacted overnight at room temperature under a hydrogen atmosphere. The solution was filtered and palladium on charcoal was washed with THF (50 mL). The solvent was evaporated and the residue (110 mg) was purified by flash chromatography using ethyl acetate as eluent to give a clear oil in 47% yield (47 mg).
LC-MS: 796.4 (M + H) ⁺ , purity 95%.

¹ H NMR (acetone-d ₆ ): δ 0.84-0.97 (m, 12H), 0.97-1.08 (m, 2H), 1.27-1.43 (m, 3H), 1 .49-1.62 (m, 4H), 1.80-1.93 (m, 1H), 1.94-2.00 (m, 1H), 2.36-2.46 (m, 1H) 2.58-2.74 (m, 2H), 2.86-2.96 (m, 3H), 2.99-3.10 (m, 2H), 3.46-3.52 (s, 3H), 3.52-3.60 (m, 2H), 3.75-3.87 (m, 2H), 3.95-4.04 (m, 1H), 4.10-4.18 ( m, 1H), 4.37-4.44 (m, 1H), 4.89-4.97 (m, 1H), 5.40-5.48 (m, 1H), 6.30-6. 40 (m, 1H), 6.76-6.83 (d J = 8.2, 1H), 6.87-7.03 (m, 2H), 7.14-7.22 (m, 1H), 7.23-7.34 (m, 3H), 7. 35-7.45 (m, 4H), 7.50-7.56 (m, 1H), 7.57-7.65 (m, 1H).

Example 11: In vitro inhibition of CYP450

Human Liver Microsomes Pooled human liver microsomes (obtained from 15 donors) were obtained from In Vitro Technologies, Inc. (Baltimore, Maryland, USA).

Preparation of PL-100 and ritonavir solution A stock solution of PL-100 was prepared at 25 mM in methanol. For the CYP3A4 assay, a 25 mM stock solution was diluted with methanol to 0.25 mM and 0.125 mM. 25 mM stock solutions and 0.25 and 0.125 mM solutions were diluted 250-fold for microsome incubation to final concentrations of 200 nM, 500 nM, and 1000 nM. A PL-100 sub-stock solution was prepared at 25 μM in methanol, diluted to 2.5 μM and 0.25 μM, and further diluted 250-fold for microsome incubation to a final concentration of 100, 10 and 1 nM.

  A stock solution of ritonavir was prepared at 25 mM in methanol. A substock solution was prepared at 25 μM in methanol. This substock solution was diluted in methanol to 2.5 μM and 0.25 μM, and further diluted 250-fold for microsome incubation to final concentrations of 100 nM, 10 nM, and 1 nM.

  Control incubations were performed in the presence of the same volume of methanol. The final methanol concentration of the incubation mixture was <1%. Selective inhibitors of CYP450 were tested in parallel as a positive control.

Testosterone 6β-hydrolase (TESH) activity After incubation of microsomes with testosterone as a substrate, TESH activity was determined by HPLC-UV analysis. Liver microsomes (final concentration 0.30 mg / ml protein) are incubated at 37 ° C. for 10 minutes and 0.1 M phosphate buffer containing NADPH-producing system, PL-100, ritonavir, or ketoconazole at an appropriate concentration. (PH 7.4) After providing various concentrations of testosterone in a 0.5 ml reaction mixture containing 1 mM EDTA and 3 mM magnesium chloride in the incubation medium containing the probe substrate, the reaction is initiated by addition of the NADPH generating system. did. The reaction was terminated with 500 μL ice-cold acetonitrile and the formation of 6β-hydroxytestosterone was quantified using a 6 point standard curve (range 2-20 nmol / mL). Three quality control (LQC, MQC, and HQC) analyzes were also performed. The relevant enzyme activity was expressed as nmol of β-hydroxytestosterone per minute / mg protein. Data were captured by a Millenium chromatography data management and storage system (version 4.0).

Michaelis-Menten Kinetics
EnzFitter software (Biosoft) is used to obtain probe substrate Km, Vmax and apparent Km ′, Vmax ′, and PL-100 in the presence of various concentrations of PL-100, ritonavir, or selective inhibitors. Ritonavir or the selective inhibitor Ki was used to calculate. Cytochrome P450 activity was plotted against substrate concentration. Nonlinear regression analysis was performed on the Michaelis-Menten model in the presence or absence of PL-100, ritonavir, or a selective inhibitor.

Lineweaver-Burk plot To determine the mode of inhibition, EnzFitter software was used to perform a linear regression of 1 / V vs. 1 / [S] using a fitted 1 / V value transformation. Created. Curve characteristics were used as an indicator of the mode of inhibition.

Ki was calculated using the equation corresponding to the mode of inhibition.
No inhibition: V = Vmax ^* [S] / (Km + [S])
Competitive inhibition: V = Vmax ^* [S] / (Km (1+ [I] / Ki) + [S])
Km ′ = Km ^* (1+ [I] / Ki)
Non-competitive inhibition: V = Vmax ^* [S] / (Km (1+ [I] / Ki)
+ [S] (1+ [I] / Ki)) =
= (Vmax / (1+ [I] / Ki) * [S]) / (Km + [S])
Vmax ′ = Vmax / (1+ [I] / Ki)
Uncompetitive inhibition: V = Vmax ^* [S] / (Km + [S] (1+ [I] / Ki)) =
= (Vmax / (1+ [I] / Ki) * [S]) / (Km / (1+ [I] / Ki) + [S])
Km ′ = Km / (1+ [I] / Ki)
Vmax ′ = Vmax / (1+ [I] / Ki)
V: Speed of enzyme reaction in the presence of inhibitor Vmax: Maximum speed Vmax ′: Maximum speed in the presence of inhibitor
[S]: Substrate concentration
[I]: Inhibitor concentration Km: Dissociation constant of enzyme substrate complex Km ′: Dissociation constant of enzyme substrate complex in the presence of inhibitor Ki: Dissociation constant of enzyme-inhibitor complex

HPLC method 6β-hydroxytestosterone column: C18, 4 μm, 3.9 × 150 mm
Detection: UV @ 254nm
Mobile phase (gradient): A: methanol, water, acetonitrile (39: 60: 1)
B: Methanol, water, acetonitrile (80: 18: 2)
Flow rate: 1 mL / min

Data calculation and statistical analysis The numerical data obtained during the study period were subjected to the mean and standard deviation of the calculation group using Excel software (Microsoft) where appropriate. Enzyme kinetic parameters (Km and Vmax) and Ki values for test articles and selective inhibitors were calculated by non-linear regression analysis using EnzFitter software. Using the EnzFitter software, line weaver-bark plots can also be created from Michaelis-Menten curve fitting and Michaelis-Menten curve fit values, thus enabling appropriate identification of inhibition modes It became.

The testosterone 6β-hydrolase activity, a selective marker for CYP3A4 / 5, was evaluated in the presence of PL-100. With a Ki of 0.445 ± 0.050 μM (R ² = 0.98: FIGS. 1-4), PL-100 could be regarded as a strong competitive inhibitor of human CYP3A4, whereas this compound was more potent than ritonavir. About 13 times less effective.

Consistent with the regression data, ritonavir had a Ki of 0.034 ± 0.005 μM (R ² = 0.98: FIGS. 1 and 2) and showed strong competitive inhibition of CYP3A4 activity.

In ketoconazole, Ki was calculated to be 0.052 ± 0.012 μM, and it was a competitive inhibitor with strong CYP3A4 activity (R ² = 0.99: FIGS. 1 to 3).

  Thus, PL-100 can be considered a strong inhibitor of CYP3A4 / 5, but has a Ki value that is 13 times higher than ritonavir and 8.5 times higher than ketoconazole.

Example 12: In vivo inhibition of CYP450

Preparation of PPL-100 mixture (40 mg / mL) Appropriate amount of test article PPL-100 in 20% ethanol, 50% propylene glycol, 0.1% Tween, and 30% water (v / v / v / v) Dissolved in the mixture to give a concentration of 40 mg / mL. The concentration was calculated taking into account the purity of the test article.

Preparation of atanazavir mixture (10 mg / mL)
Atanazavir was dissolved in a mixture of 20% ethanol, 50% propylene glycol, 0.1% Tween, and 30% water (v / v / v / v) to give a concentration of 10 mg / mL.

Preparation of dosing solution The dosing solution was prepared immediately prior to dosing as follows: Briefly, 4 mL of PPL-100 mixture (40 mg / mL) was mixed with 4 mL of atanazavir mixture (10 mg / mL).

Animals Sprague Dawley rats (Rattus norvegicus) 7-8 weeks old at the start of dosing were used for the study (Charles River Canada Inc., Montreal, PQ). Animals received atanazavir (25 mg / kg) and PPL-100 (100 mg / kg). Six female rats were used at each time point. Animals were administered a mixture containing atanazavir (5 mg / mL) and PPL-100 (20 mg / mL) at a dose volume of 5 mL per kg body weight. The summary of treatment is illustrated in Table A below.

Blood samples were collected at 6 time points. Rats were bled as summarized in Table B. Blood was collected from the orbital sinus of each rat for the purpose of collecting the samples indicated above. Each blood sample (approximately 0.4 mL) was collected in a tube containing the anticoagulant K ₂ EDTA. Time (acting time in combination with days and time of administration) was recorded for each sample. After collection, the sample was inverted for about 10 minutes and then the sample was centrifuged at 2000 rpm for 20 minutes under freezing (2-8 ° C.). Plasma obtained from each sample is collected and stored frozen (approximately -80 ° C) until analysis.

  At the time of analysis, proteins were extracted from plasma samples and PL-100 (active ingredient released from PPL-100 under physiological conditions) or atanazavir was detected by HPLC-UV-MSD (1100 series, Hewlett Packard).

  The results of this analysis shown in FIGS. 5 and 6 indicate that PL-100 (PPL-100) reduces atanazavir metabolism in vivo. PL-100 (PPL-100) successfully increases the plasma concentration of atanazavir in 24 hours.

Example 13 Microsome Stability An in vitro study was conducted to demonstrate that PL-100 improves the stability of protease inhibitors in microsomes.

  The protease inhibitors tested were as follows: atanazavir (ATV), lopinavir (LPV), saquinavir (SQV), amprenavir (APV), nelfinavir (NFV), and indinavir (IDV).

  Except for the experiment using atanazavir (in this case, the concentration of atanazavir was 1.0 μM and the concentration of PL-10 was 2.0 μM), the concentrations of protease inhibitor and PL-100 were 10 μM.

  After incubating each protease inhibitor with microsomes, the percentage of parent remaining (original protease inhibitor) is determined. Measurements were taken at 60 minutes. Protease inhibitors are easily metabolized to daughter molecules in the microsome and the amount of the original protease inhibitor is reduced, so the percentage of remaining parent quantifies the degree of stability of the protease inhibitor. The greater the percentage of remaining parent, the greater the stability of the protease inhibitor in the microsome.

  The percentage of parent remaining was determined for each protease inhibitor in the presence or absence of PL-100. As a control, the percent of protease inhibitor remaining was measured in the presence of ritonavir (RTV) to compare the boosting effect between PL-100 and RTV.

  The experimental results (FIG. 7) demonstrate that PL-100 can improve the stability in the microsomes of all tested protease inhibitors. Thus, PPL-100 is a potential booster of these protease inhibitors in vivo.

Claims (18)

a) Lysine-based compounds of formula I

Or a pharmaceutically acceptable salt thereof,
(Where
n is 3 or 4;
X and Y are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F _{, Cl, Br, I, -CF} 3, -OCF 3, -CN, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4 and, - is selected from the group consisting of CH ₂ OH, or X and Y, together, are selected from the group consisting of the formulas -OCH ₂ O-methylenedioxy group and the formula -OCH ₂ CH ₂ O- ethylenedioxy group An alkylenedioxy group,
R ₆ is a straight chain alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 3 in the alkyl portion. Selected from the group consisting of cycloalkylalkyl groups having
R ₃ is H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and the formula R _3A —CO Wherein R _3A is a linear or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl moiety; cycloalkylalkyl groups having 1-3 carbon atoms in the 3 to 6 carbon atoms and an alkyl moiety of 1 to 6 alkyl group carbon atoms, _{tetrahydro-3-furanyloxy,} -CH 2 OH, -CF _{3, -CH 2 CF 3, -CH} 2 CH 2 CF 3, pyrrolidinyl, piperidinyl, _{4-morpholinyl, CH 3 O 2 C-, CH} 3 O 2 CCH 2 -, acetyl _{-OCH 2 CH 2 -, HO 2} CCH -, 3-hydroxyphenyl, _{4-hydroxyphenyl, 4-CH 3 OC 6 H} 4 CH 2 -, CH 3 NH -, (CH 3) 2 N -, (CH 3 CH 2) 2 N -, (CH 3 _{CH 2 CH 2) 2 N-,} HOCH 2 CH 2 NH-, CH 3 OCH 2 O-, CH 3 OCH 2 CH 2 O-, C 6 H 5 CH 2 O-, 2- pyrrolyl, 2-pyridyl, 3 -Pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group of the formula

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of:

A substituted pyridyl group selected from the group consisting of:

And the group of the following formula

Selected from the group consisting of
X ′ and Y ′ are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms , becomes _{F, Cl, Br, I,} from _{-CF 3, -NO 2, -NR 4} R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4, and _-CH 2 OH Selected from the group,
R ₄ and R ₅ are the same or different and are H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl of 3 to 6 carbon atoms. Selected from the group consisting of:
R ₂ is a diphenylmethyl group of formula IV,

Naphthyl of formula V -1-CH ₂ - group,

Naphthyl of the formula VI -2-CH ₂ - group,

A biphenylmethyl group of the formula VII,

And anthryl of formula VIII -9-CH ₂ - group,

Selected from the group consisting of
R ₁ is H or a physiologically cleavable unit)
b) a drug that is acted upon by cytochrome P450 monooxygenase, and c) a pharmaceutically acceptable carrier;
(Wherein the ratio (w / w) of said lysine-based compound or a pharmaceutically acceptable salt thereof to a drug acted on by cytochrome P450 monooxygenase is between about 4: 1 and about 1: 1. is there)
A pharmaceutical composition comprising: The lysine base compound is a compound of formula II

Or the pharmaceutical composition of Claim 1 which is its pharmaceutically acceptable salt. A claim 1 or a pharmaceutical composition according to claim 2, wherein, _{R 1 is, H, (HO) 2 P} (O) and _{(MO) 2 P (O)} , and wherein _R 1A -CO Wherein R _1A is a linear or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl moiety; cycloalkylalkyl groups having 1-3 carbon atoms in the 3 to 6 carbon atoms and an alkyl moiety of 1 to 6 alkyl group carbon _{atoms, -CH 2 OH, CH 3 O} 2 C-, CH ₃ O ₂ CCH ₂ -, acetyl _{-OCH 2 CH 2 -, HO 2} CCH 2 -, 2- hydroxyphenyl, 3-hydroxyphenyl, _{4-hydroxyphenyl, (CH 3) 2 NCH 2} -, (CH 3) 2 CHCH _(NH 2) -, HO _{CH 2 CH 2 NH-, CH 3} OCH 2 O-, CH 3 OCH 2 CH 2 O-, 2- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro -3 -Pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group of the formula

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of:

A substituted pyridyl group selected from the group consisting of:

And the group of the following formula

A pharmaceutical composition wherein M is an alkali metal or alkaline earth metal and X ′, Y ′, R ₄ and R ₅ are as defined in claim 1. The pharmaceutical composition according to claim 1, wherein X, Y, n, R1, R2, R3, R6, X ', and Y' are as defined below for each of the lysine-based compounds of formula I. object.

  The drug acted by the cytochrome P450 monooxygenase is selected from the group consisting of atanazavir (ATV), lopinavir (LPV), saquinavir (SQV), amprenavir (APV), nelfinavir (NFV), and indinavir (IDV). The pharmaceutical composition according to any one of claims 1 to 4.   The pharmaceutical composition according to any one of claims 1 to 5, wherein the ratio (w / w) of the lysine base compound to the drug acted on by the cytochrome P450 monooxygenase is about 4: 1.   The pharmaceutical composition according to any one of claims 1 to 6, wherein the cytochrome P450 monooxygenase is CYP3A4. a) Lysine-based compounds of formula I

Or a pharmaceutically acceptable salt thereof, wherein
n is 3 or 4;
X and Y are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, F _{, Cl, Br, I, -CF} 3, -OCF 3, -CN, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, -COR 4 and, - is selected from the group consisting of CH ₂ OH, or X and Y, together, are selected from the group consisting of the formulas -OCH ₂ O-methylenedioxy group and the formula -OCH ₂ CH ₂ O- ethylenedioxy group An alkylenedioxy group,
R ₆ is a straight chain alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 3 in the alkyl portion. Selected from the group consisting of cycloalkylalkyl groups having carbon atoms;
R ₃ is H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and the formula R _3A —CO Wherein R _3A is a linear or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl moiety; cycloalkylalkyl groups having 1-3 carbon atoms in the 3 to 6 carbon atoms and an alkyl moiety of 1 to 6 alkyl group carbon atoms, _{tetrahydro-3-furanyloxy,} -CH 2 OH, -CF _{3, -CH 2 CF 3, -CH} 2 CH 2 CF 3, pyrrolidinyl, piperidinyl, _{4-morpholinyl, CH 3 O 2 C-, CH} 3 O 2 CCH 2 -, acetyl _{-OCH 2 CH 2 -, HO 2} CCH -, 3-hydroxyphenyl, _{4-hydroxyphenyl, 4-CH 3 OC 6 H} 4 CH 2 -, CH 3 NH -, (CH 3) 2 N -, (CH 3 CH 2) 2 N -, (CH 3 _{CH 2 CH 2) 2 N-,} HOCH 2 CH 2 NH-, CH 3 OCH 2 O-, CH 3 OCH 2 CH 2 O-, C 6 H 5 CH 2 O-, 2- pyrrolyl, 2-pyridyl, 3 -Pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, phenyl group of the formula

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of:

A substituted pyridyl group selected from the group consisting of:

And the group of the following formula

Selected from the group consisting of
X ′ and Y ′ are the same or different, H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms _{, F, Cl, Br, I} , -CF 3, -NO 2, -NR 4 R 5, -NHCOR 4, -OR 4, -SR 4, -COOR 4, the group consisting of -COR ₄ and _-CH 2 OH Selected from
R ₄ and R ₅ are the same or different and are H, a linear alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkyl of 3 to 6 carbon atoms. Selected from the group consisting of:
R ₂ is a diphenylmethyl group of formula IV,

Naphthyl of formula V -1-CH ₂ - group,

Naphthyl of the formula VI -2-CH ₂ - group,

A biphenylmethyl group of the formula VII,

And anthryl of formula VIII -9-CH ₂ - group,

Selected from the group consisting of
R ₁ is H or a physiologically cleavable unit);
b) a drug acted on by cytochrome P450 monooxygenase (where the ratio (w / w) of said lysine-based compound or pharmaceutically acceptable salt thereof to the drug acted on by cytochrome P450 monooxygenase is about Between 4: 1 and about 1: 1)
A pharmaceutical combination comprising The lysine base compound is a compound of formula II

Or a pharmaceutical combination according to claim 8, which is a pharmaceutically acceptable salt thereof. A pharmaceutical combination according to claim 8 or claim 9, wherein, _{R 1 is, H, (HO) 2 P} (O) and _{(MO) 2 P (O)} , and wherein _R 1A -CO Wherein R _1A is a linear or branched alkyl group of 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl moiety; cycloalkylalkyl groups having 1-3 carbon atoms in the 3 to 6 carbon atoms and an alkyl moiety of 1 to 6 alkyl group carbon _{atoms, -CH 2 OH, CH 3 O} 2 C-, CH ₃ O ₂ CCH ₂ -, acetyl _{-OCH 2 CH 2 -, HO 2} CCH 2 -, 2- hydroxyphenyl, 3-hydroxyphenyl, _{4-hydroxyphenyl, (CH 3) 2 NCH 2} -, (CH 3) 2 CHCH (NH ₂ )- , HOCH ₂ CH ₂ NH—, CH ₃ OCH ₂ O—, CH ₃ OCH ₂ CH ₂ O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro- 3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of the formula

A picolyl group selected from the group consisting of:

A picolyloxy group selected from the group consisting of:

A substituted pyridyl group selected from the group consisting of:

And a group of the formula

9. A pharmaceutical combination as defined in claim 8 wherein M is an alkali metal or alkaline earth metal and X ′, Y ′, R ₄ and R ₅ are selected from the group consisting of 9. The pharmaceutical of claim 8, wherein X, Y, n, R1, R2, R3, R6, X ', and Y' are as defined below for each of the lysine-based compounds of formula I. combination.

  The drug affected by cytochrome P450 monooxygenase is selected from the group consisting of atanazavir (ATV), lopinavir (LPV), saquinavir (SQV), amprenavir (APV), nelfinavir (NFV), and indinavir (IDV). The pharmaceutical combination according to any one of claims 8 to 11.   13. The pharmaceutical combination according to any of claims 8 to 12, wherein the ratio (w / w) of the lysine-based compound to the drug acted upon by the cytochrome P450 monooxygenase is about 4: 1.   The pharmaceutical combination according to any one of claims 8 to 13, wherein the cytochrome P450 monooxygenase is CYP3A4. At least one lysine-based compound of formula I in the manufacture of a medicament for the treatment or prevention of HIV infection or the treatment or prevention of AIDS

Or a pharmaceutically acceptable salt thereof and a drug acted on by cytochrome P450 monooxygenase (wherein n, X, Y, X ′, Y ′, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , And R ₆ is defined in claim 1, wherein the ratio (w / w) of the lysine-based compound to the drug acted on by the cytochrome P450 monooxygenase is between about 4: 1 and about 1: 1. Use).   A method of treating or preventing HIV infection or a method of treating or preventing AIDS, wherein the pharmaceutical composition as defined in claim 1 or the pharmaceutical combination as defined in claim 8 is administered to a mammal in need thereof A method comprising: a) Lysine-based compounds of formula I

Wherein n, X, Y, X ′, Y ′, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ are defined in claim 1) or pharmaceutically acceptable And b) one or more drugs acted on by cytochrome P450 monooxygenase (wherein the lysine-based compound reduces the metabolism of one or more drugs acted on by cytochrome P450 monooxygenase) A ratio (w / w) of the lysine-based compound to the one or more drugs is between about 4: 1 and about 1: 1)
A method of treating or preventing HIV infection or a method of treating or preventing AIDS, comprising administering   A method for improving the pharmacokinetics of a drug affected by cytochrome P450 monooxygenase, wherein said lysine-based compound of formula I and said cytochrome P450 mono are effective to inhibit cytochrome P450 monooxygenase. Administering an amount of a drug affected by oxygenase to a human in need thereof, wherein the ratio (w / w) of the lysine base compound to the drug is between about 4: 1 and about 1: 1. Is that way.

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